Lynparza

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LYNPARZA (LYNPARZA)

Composition:

Active substance: olaparib;

One film-coated tablet contains 100 mg or 150 mg of olaparib;

Excipients: copovidone, colloidal anhydrous silicon dioxide, mannite (E 421), sodium stearyl fumarate;

Tablet coating for 100 mg tablets: hypromellose, polyethylene glycol 400, titanium dioxide (E 171), iron oxide yellow (E 172);

Tablet coating for 150 mg tablets: hypromellose, polyethylene glycol 400, titanium dioxide (E 171), iron oxide yellow (E 172), iron oxide black (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics:

Film-coated tablets of 100 mg: yellow to dark yellow, oval-shaped, biconvex, film-coated tablets with "OP 100" engraved on one side;

Film-coated tablets of 150 mg: green to green-grey, oval-shaped, biconvex, film-coated tablets with "OP 150" engraved on one side.

Pharmacotherapeutic group

Antineoplastic and immunomodulating medicinal agents. Antineoplastic agents. Other antineoplastic agents. Poly (ADP-ribose) polymerase (PARP) inhibitors. Olaparib. ATC code L01XK01.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action and Pharmacodynamic Effects

Olaparib is a potent inhibitor of human poly (ADP-ribose) polymerase enzymes (PARP-1, PARP-2, and PARP-3), which suppresses the growth of certain tumor cell lines in vitro and tumor growth in vivo when administered alone or in combination with conventional chemotherapeutic agents or novel hormonal agents (NHAs).

For effective PARP-mediated repair, after chromatin modification, the PARP enzyme must auto-modify and dissociate from DNA to allow access of base excision repair (BER) enzymes to the site of DNA break. When olaparib binds to the active site of the PARP enzyme attached to DNA, it prevents the dissociation of PARP, thereby trapping it on the DNA and blocking DNA repair. In dividing cells, this leads to collision of the replication fork with the PARP-DNA complex and results in double-strand DNA breaks (DSBs). In normal cells, efficient repair of these DSBs is mediated via the homologous recombination repair (HRR) pathway. In cancer cells lacking functional components required for effective homologous recombination repair (HRR), such as BRCA1 or 2 genes, repair of DSBs cannot be accurate or efficient, leading to a significant homologous recombination deficiency (HRD). Instead, alternative repair pathways such as classical non-homologous end joining (NHEJ) are activated, which are associated with a higher risk of errors, resulting in high-level genomic instability. After several rounds of replication, genetic instability may reach critical levels, potentially leading to cancer cell death, as DNA in cancer cells is already more damaged than in normal cells. Processes along the HRR pathway may be disrupted through other mechanisms, although the underlying aberrations and penetrance are not fully understood. The absence of a fully functional HRR pathway is one of the main factors contributing to the sensitivity of ovarian cancer, and possibly other cancers, to platinum-based agents.

In BRCA1/2-deficient in vivo models, when olaparib was administered after platinum-based agents, tumor progression was slower and overall survival was higher compared to treatment with platinum agents alone, correlating with the duration of olaparib maintenance therapy.

Combined Antitumor Effect of NHAs

Preclinical data from prostate cancer models demonstrated a combined antitumor effect when PARP inhibitors were used concomitantly with novel hormonal agents. PARP is involved in enhancing signaling through the androgen receptor (AR) pathway, increasing suppression of AR target genes during inhibition of PARP/AR signaling pathways. Other preclinical studies have shown that treatment with NHAs suppresses transcription of certain HRR genes, thereby inducing HRR deficiency and increasing sensitivity to PARP inhibitors via non-genetic mechanisms.

Detection of BRCA1/2 Gene Mutations

Genetic testing should be performed by experienced laboratory personnel using a validated method. In various studies, local or central laboratories analyzed blood and/or tumor samples to detect germline and/or somatic BRCA1/2 gene mutations. In most studies, DNA extracted from tumor or blood samples was analyzed, with circulating tumor DNA (ctDNA) analysis conducted in exploratory settings. Depending on the testing method used and international consensus on mutation classification, BRCA1/2 mutations were classified as deleterious/suspected deleterious or pathogenic/likely pathogenic. A positive homologous recombination deficiency (HRD) status can be defined by the presence of a BRCA1/2 gene mutation classified as deleterious/suspected deleterious or pathogenic/likely pathogenic. Detection of these mutations may be combined with a positive HRD score (below) to determine a positive HRD status.

Detection of Genomic Instability

Genomic alterations associated with homologous recombination deficiency, investigated in PAOLA-1, include genomic loss of heterozygosity, telomeric allelic imbalance, and large-scale transitions, which are continuous variables with predefined criteria and scoring. The composite genomic instability score (GIS, also referred to as HRD score) is determined when combined values and corresponding scores are used to assess the extent of specific genomic aberrations accumulated in tumor cells. A lower score indicates a lower likelihood of homologous recombination deficiency (HRD) in tumor cells, while a higher score indicates a greater likelihood of HRD in tumor cells at the time of sample collection, relative to the impact of DNA-damaging agents. Validated cutoff thresholds should be used to determine a positive GIS status.

A positive HRD status can be defined by the composite genomic instability score for genomic changes associated with homologous recombination deficiency, tested by experienced laboratory personnel using a validated assay.

Clinical Efficacy and Safety

First-Line Maintenance Therapy in Advanced Ovarian Cancer with BRCA Mutation

Study SOLO1

The safety and efficacy of olaparib as maintenance therapy were evaluated in patients with newly diagnosed advanced (Stage III and IV according to the International Federation of Gynecology and Obstetrics [FIGO]) high-grade serous or endometrioid ovarian cancer and a BRCA1/2 mutation (BRCA1/2m) following completion of first-line platinum-based chemotherapy in a randomized, double-blind, placebo-controlled, multicenter Phase III trial. In this study, 391 patients were randomized in a 2:1 ratio to receive either Lynparza (300 mg [2 tablets of 150 mg] twice daily) or placebo. Patients were stratified by response to first-line platinum-based chemotherapy: complete response (CR) or partial response (PR). Treatment continued until radiologically confirmed disease progression, occurrence of unacceptable toxicity, or for up to 2 years. Patients who maintained a complete clinical response (i.e., no radiological evidence of disease) were treated for up to 2 years. However, patients with stable residual disease (i.e., no signs of progression) could continue receiving Lynparza beyond 2 years.

Patients with germline or somatic BRCA1/2 mutations were prospectively identified by blood testing in a local (n = 208) or central laboratory (n = 181), or by tumor sample testing in a local laboratory (n = 2). Central laboratory testing for germline mutations identified deleterious or suspected deleterious mutations in 95.3% (365/383) and 4.7% (18/383) of patients, respectively. Large BRCA1/2 gene rearrangements were detected in 5.5% (21/383) of randomized patients. The gBRCAm status of enrolled patients, determined in a local laboratory, was retrospectively confirmed in a central laboratory. Retrospective tumor sample analyses were performed in the central laboratory. Successful results were obtained in 341 patients, 95% of whom had the required mutation (known [n = 47] or likely pathogenic [n = 277]), and in 2 patients with gBRCAwt, only sBRCAm was confirmed. In the SOLO1 study, 389 patients had a germline BRCA1/2m and 2 had a somatic BRCA1/2m.

Demographic data and baseline characteristics were generally comparable between the olaparib and placebo treatment groups. The median age in both groups was 53 years. Ovarian cancer was the primary tumor in 85% of patients. The most common histological type was serous carcinoma (96%). Endometrioid carcinoma was reported in 2% of patients. The majority of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (78%). Data on patients with ECOG performance status 2–4 are not available. Primary cytoreductive surgery was performed in 63% of patients, with no macroscopic residual disease in 75% of these. Interval cytoreduction was performed in 35% of patients, with no macroscopic residual disease in 82% of these. Seven patients with Stage IV disease did not undergo cytoreductive surgery. All patients received first-line platinum-based therapy. At study entry, 73% and 77% of patients in the olaparib and placebo groups, respectively, had no evidence of disease (i.e., CR), defined by investigator assessment as absence of disease on radiological imaging and normal cancer antigen 125 (CA-125) levels. PR, defined as presence of measurable or non-measurable lesions at study entry or elevated CA-125 levels, was observed in 27% and 23% of patients in the olaparib and placebo groups, respectively. Ninety-three percent (93%) of patients were randomized within 8 weeks of their last platinum-based chemotherapy. Patients who received bevacizumab were excluded from the study; therefore, there are no data on the safety and efficacy of olaparib in patients previously treated with bevacizumab. Data in patients with somatic BRCA gene mutations are very limited.

The primary endpoint was progression-free survival (PFS), defined as the time from randomization to disease progression, as assessed by the investigator using modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, or death. Secondary efficacy endpoints included time from randomization to second progression or death (PFS2), overall survival (OS), time to discontinuation or death (TDT), time to first subsequent therapy or death (TFST), and health-related quality of life (HRQoL). Tumor assessments were performed radiologically at baseline, every 12 weeks for 3 years, and then every 24 weeks from the date of randomization until objective disease progression.

The study demonstrated clinically relevant and statistically significant improvement in PFS with olaparib compared to placebo, as assessed by the investigator. The investigator-assessed PFS was independently verified by blinded independent central review (BICR). A descriptive analysis performed seven years after the last patient was randomized showed clinically meaningful benefits in overall survival (OS), favoring the olaparib group. Efficacy results are presented in Table 1.

Table 1

Efficacy Results in Patients with Newly Diagnosed Advanced Ovarian Cancer and BRCA1/2 Mutation in Study SOLO1

N.D. – not reached; CI – confidence interval; PFS – progression-free survival;

PFS2 – time to second progression or death; OS – overall survival; TFST – time from randomization to first subsequent anti-cancer therapy or death.

a According to Kaplan–Meier estimates, the proportions of patients without disease progression at 24 and 36 months were 74% and 60% in the olaparib group and 35% and 27% in the placebo group. The median duration of further follow-up in both groups was 41 months.

b If the value is < 1, olaparib is more effective. The analysis was performed using the Cox proportional hazards model, which included response to prior platinum-based chemotherapy (CR or PR) as a covariate.

c Of the 97 patients in the placebo group who received subsequent therapy, 58 (60%) received a PARP inhibitor.

d According to Kaplan–Meier estimates, the proportion of patients alive at 84 months was 67% in the olaparib group and 47% in the placebo group.

Assessment of disease characteristics at the time of patient enrollment in the study yielded results consistent between patient subgroups. In patients with investigator-determined CR, the HR was 0.34 (95% CI 0.24–0.47). Median PFS was not reached in the group receiving olaparib and was 15.3 months in the placebo group. At 24 and 36 months, CR was maintained in 68% and 45% of patients in the olaparib group and in 34% and 22% of patients in the placebo group, respectively. In patients with PR at enrollment, PFS was achieved with an HR of 0.31 (95% CI 0.18, 0.52; median PFS was 30.9 months in the olaparib group and 8.4 months in the placebo group). In patients with PR at enrollment, either CR was achieved (in 15% of the olaparib group and 4% of the placebo group at 24 months; CR was maintained for 36 months) or PR/stable disease was maintained (in 43% of the olaparib group and 15% of the placebo group at 24 months; in 17% of the olaparib group and 15% of the placebo group at 36 months). The proportions of patients in whom disease progressed within 6 months after the last platinum-based chemotherapy were 3.5% in the olaparib group and 8.4% in the placebo group.

Maintenance therapy of platinum-sensitive recurrent ovarian cancer

Study SOLO2

The safety and efficacy of olaparib as maintenance therapy were evaluated in a randomized, double-blind, placebo-controlled, phase III study in patients with platinum-sensitive recurrent ovarian, fallopian tube, or primary peritoneal cancer with a germline BRCA1/2 gene mutation. The study compared the efficacy of maintenance therapy with Lynparza (300 mg [2 tablets of 150 mg] twice daily) administered until disease progression, versus placebo, in 295 patients with high-grade serous or endometrioid platinum-sensitive recurrent ovarian cancer (randomized in a 2:1 ratio: 196 patients received olaparib and 99 received placebo), who had achieved a response (CR or PR) following completion of platinum-based chemotherapy.

Eligible patients had received two or more prior platinum-based chemotherapy regimens and experienced recurrence >6 months after the end of the penultimate platinum-based chemotherapy. Patients must not have previously received olaparib or any other PARP inhibitors. Prior bevacizumab use was allowed, but not immediately before randomization.

All patients had a germline BRCA1/2 gene mutation at study entry. BRCA1/2 mutations were identified via blood testing at a local or central laboratory (Myriad) or via tumor tissue testing at a local laboratory. Large BRCA1/2 gene rearrangements were detected in 4.7% (14/295) of randomized patients.

Demographic and baseline characteristics were generally comparable between the olaparib and placebo groups. The median age in both groups was 56 years. Ovarian cancer was the primary tumor in >80% of patients. The most common histologic type was serous carcinoma (>90%). Endometrioid carcinoma was reported in 6% of patients. In the olaparib group, 55% of patients had previously received only 2 lines of chemotherapy, and 45% had received 3 or more lines. In the placebo group, 61% had previously received only 2 lines of chemotherapy, and 39% had received 3 or more lines. The majority of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (81%). Data on patients with ECOG performance status 2–4 are not available. The intervals between platinum treatments were >12 months in 60% and >6–12 months in 40% of patients. Response to prior platinum-based chemotherapy was complete in 47% and partial in 53% of patients. Prior bevacizumab use was reported in 17% and 20% of patients in the olaparib and placebo groups, respectively.

The primary endpoint was PFS, assessed by the investigator using RECIST version 1.1. Secondary efficacy endpoints included PFS2, OS, TDT, TFST, TSST, and HRQoL.

The study met its primary objective: a statistically significant improvement in investigator-assessed PFS was demonstrated in patients receiving olaparib compared to those receiving placebo, with a hazard ratio (HR) of 0.30 (95% CI 0.22–0.41; p < 0.0001; median 19.1 months in the olaparib group versus 5.5 months in the placebo group). The investigator-assessed PFS result was confirmed by blinded independent central radiological review of PFS (HR 0.25; 95% CI 0.18–0.35; p < 0.0001; median 30.2 months in the olaparib group versus 5.5 months in the placebo group). At 2 years, disease progression was absent in 43% of patients receiving olaparib and in only 15% of patients receiving placebo.

Summary results of objective assessment for the primary endpoint in patients with platinum-sensitive recurrent ovarian cancer and germline BRCA1/2 mutation in study SOLO2 are presented in Table 2.

Table 2

Summary results of objective assessment for the primary endpoint in patients with platinum-sensitive recurrent ovarian cancer and germline BRCA1/2 mutation in study SOLO2

a HR – hazard ratio. If the value is < 1, olaparib is more effective. The analysis was performed using a Cox proportional hazards model, which included response to prior platinum-based chemotherapy (CR or PR) and time to disease progression (from > 6 to 12 months and > 12 months) during the penultimate platinum-based chemotherapy as covariates.

PFS – progression-free survival; CI – confidence interval.

At the final overall survival analysis (61% data maturity), the hazard ratio (HR) was 0.74 (95% CI 0.54–1.00; p = 0.0537; median OS was 51.7 months for olaparib versus 38.8 months for placebo); thus, statistically significant improvement in OS was not achieved. Results of the assessment of secondary endpoints TFST and PFS2 demonstrated consistent and statistically significant clinical benefit with olaparib compared to placebo. Results for OS, TFST, and PFS2 are presented in Table 3.

Table 3

Summary of efficacy results for key secondary endpoints in patients with platinum-sensitive, relapsed ovarian cancer and a germline BRCA1/2 mutation in the SOLO2 study

* Without corrections for plurality.

N.D. – not reached; CI – confidence interval; PFS2 – time from randomization to second progression or death; TFST – time from randomization to start of first subsequent therapy or death.

aHR – hazard ratio. If the value is < 1, olaparib is more effective. Analysis was performed using the Cox proportional hazards model, which included response to prior platinum-based chemotherapy (CR or PR) and time to disease progression (from > 6 to 12 months and > 12 months) during the penultimate platinum-based chemotherapy as covariates.

Among enrolled patients with measurable disease (with target lesions at study entry), objective response was achieved in 41% of patients in the group receiving the medicinal product Lynparza and in 17% of patients in the placebo group. Among patients receiving treatment with the medicinal product Lynparza and enrolled in the study with evidence of disease (with target or non-target lesions at study entry), complete response was achieved in 15.0%, and among patients receiving placebo, complete response was achieved in 9.1%.

At the time of PFS analysis, median duration of treatment was 19.4 months in the olaparib group and 5.6 months in the placebo group. The majority of patients continued to receive olaparib at the initial dose (300 mg twice daily). The rates of discontinuation, dose reduction, and drug withdrawal due to adverse events were 45.1%, 25.1%, and 10.8%, respectively. Most discontinuations occurred within the first 3 months, and dose reductions occurred within the first 3–6 months of treatment. The adverse reactions most frequently leading to discontinuation or dose reduction were anemia, nausea, and vomiting.

Patient-reported outcomes were assessed using change from baseline in the trial outcome index score of the Functional Assessment of Cancer Therapy-Ovarian (FACT-O) questionnaire. No differences in outcomes were observed between patients receiving olaparib and those receiving placebo.

Study 19 (D0810C00019)

In a large randomized, double-blind, placebo-controlled phase II study (Study 19), the safety and efficacy of olaparib as maintenance therapy were evaluated in patients with platinum-sensitive recurrent ovarian cancer, including fallopian tube cancer or primary peritoneal cancer, after two or more lines of platinum-based chemotherapy. The study compared the efficacy of maintenance therapy with the medicinal product Lynparza administered until disease progression versus placebo in 265 patients (136 receiving olaparib and 129 receiving placebo) with platinum-sensitive, high-grade serous ovarian cancer who achieved response (CR or PR) following completion of platinum-based chemotherapy. The primary endpoint was PFS, assessed by the investigator using RECIST version 1.0. Secondary efficacy endpoints included OS, disease control rate (DCR), defined as confirmed CR/PR + SD (stable disease), HRQoL (health-related quality of life), and disease-related symptoms. Exploratory assessments of TFST and TSST were also performed.

Patients enrolled had recurrence > 6 months after completion of the penultimate platinum-based chemotherapy. Confirmation of BRCA1/2 gene mutation was not required for study entry (the BRCA gene mutation status in some patients was determined retrospectively). Patients must not have previously received olaparib or other PARP inhibitors. Patients could have previously, but not immediately prior to randomization, received bevacizumab. Re-treatment with olaparib after disease progression on olaparib was not permitted.

Patients with BRCA1/2 gene mutations were identified by testing for germline mutations in blood at a local laboratory or centrally by Myriad, or by tumor tissue testing using Foundation Medicine methodology. Large BRCA1/2 gene rearrangements were detected in 7.4% (10/136) of randomized patients.

Demographic data and baseline characteristics were generally comparable between the olaparib and placebo groups. Median age in both groups was 59 years. Ovarian cancer was the primary tumor in 86% of patients. In the olaparib group, 44% of patients had previously received only 2 lines of therapy, and 56% had received 3 or more lines of therapy. In the placebo group, 49% of patients had previously received only 2 lines of chemotherapy, and 51% had received 3 or more lines of chemotherapy. The majority of patients had an ECOG performance status of 0 (77%). Data on patients with ECOG performance status 2–4 are not available. The intervals between platinum treatments were > 12 months in 60% and > 6–12 months in 40% of patients. Response to prior platinum-based chemotherapy was complete in 45% and partial in 55% of patients. In the olaparib and placebo groups, 6% and 5% of patients, respectively, had previously received bevacizumab.

The study met its primary objective: a statistically significant improvement in PFS was observed in the overall population among patients receiving olaparib compared to those receiving placebo, with a hazard ratio (HR) of 0.35 (95% CI 0.25–0.49; p < 0.00001; median 8.4 months in the olaparib group and 4.8 months in the placebo group). The final OS assessment (data cutoff date: May 9, 2016), with 79% data maturity, showed a hazard ratio between the olaparib and placebo groups of 0.73 (95% CI 0.55–0.95; p = 0.02138 [did not meet the prespecified significance level of < 0.0095]; median 29.8 months in the olaparib group and 27.8 months in the placebo group). Treatment for ≥ 2 years was received by 23.5% (n = 32/136) of patients in the olaparib group and 3.9% (n = 5/128) of patients in the placebo group. Despite the limited number of patients, treatment for ≥ 5 years was received by 13.2% (n = 18/136) of patients in the olaparib group and 0.8% (n = 1/128) of patients in the placebo group.

A pre-planned subgroup analysis revealed that patients with ovarian cancer and BRCA1/2 gene mutation (n = 136; 51.3%, including 20 patients with somatic BRCA1/2 mutation in tumor) constituted the subgroup deriving the greatest clinical benefit from olaparib monotherapy maintenance. A favorable, though smaller, effect was also observed in patients with BRCA1/2 wild-type gene or variants of uncertain significance (BRCA1/2wt/VUS). No strategy for multiple subgroup assessments was implemented.

Summary results of objective assessment by primary endpoint in patients with platinum-sensitive recurrent ovarian cancer with BRCA1/2 gene mutation and BRCA1/2wt/VUS variant in Study 19 are presented in Table 4. Results from all patients in Study 19 are presented in Table 4.

Table 4

Summary results of objective assessment by primary endpoint in all patients and in patients with platinum-sensitive recurrent ovarian cancer with BRCA1/2 gene mutation and BRCA1/2wt/VUS variant in Study 19

PFS – progression-free survival; CI – confidence interval; n.r. – not reached.

a All patients belong to the following subgroups: the BRCA1/2 gene mutation subgroup, the BRCA1/2wt/VUS variant subgroup, and the subgroup with unknown BRCA1/2 gene mutation status (11 patients with unknown mutation status were not included in the table as a separate subgroup).

b HR – hazard ratio. If the value is < 1, olaparib is more effective. The analysis was performed using the Cox proportional hazards model with the following factors: treatment, ethnicity, platinum sensitivity, and response to the last platinum-based therapy.

Summary results of objective assessment according to key secondary endpoints in patients with platinum-sensitive recurrent ovarian cancer carrying a BRCA1/2 gene mutation or the BRCA1/2wt/VUS variant in Study 19 are presented in Table 5. Results obtained in all patients in Study 19 are presented in Table 5.

Table 5

Summary results of objective assessment according to key secondary endpoints in all patients and in patients with platinum-sensitive recurrent ovarian cancer carrying a BRCA1/2 gene mutation or the BRCA1/2wt/VUS variant in Study 19

OS – overall survival; CI – confidence interval; TFST – time from randomization to start of first subsequent therapy or death.

* No multiplicity adjustment strategies were applied for subgroup analyses or for analysis of TFST in all patients.

a All patients belong to the following subgroups: BRCA1/2 mutation subgroup, BRCA1/2wt/VUS variant subgroup, and subgroup with unknown BRCA1/2 mutation status (11 patients with unknown mutation status were not included in the table as a separate subgroup).

b HR – hazard ratio. If the value is < 1, olaparib is more effective. The analysis was performed using the Cox proportional hazards model with the following factors: treatment, ethnicity, sensitivity to platinum agents, and response to the most recent platinum-based therapy.

c Approximately one-quarter of patients in the BRCA mutation subgroup who received placebo (14/62; 22.6%) subsequently received a PARP inhibitor.

At the time of PFS analysis, the median duration of treatment was 8 months in the olaparib group and 4 months in the placebo group. The majority of patients continued olaparib at the initial dose. The rates of treatment discontinuation, dose reduction, and drug withdrawal due to adverse events were 34.6%, 25.7%, and 5.9%, respectively. Treatment discontinuation and dose reduction most commonly occurred during the first 3 months of treatment. The most frequent adverse reactions leading to treatment discontinuation or dose reduction were nausea, anemia, vomiting, neutropenia, and fatigue. The incidence of adverse reactions in the form of anemia was 22.8% (≥ grade 3 according to CTCAE, 7.4%).

Patient-reported outcomes were assessed based on the frequency of improvements and worsening in the trial outcome index and the ovarian cancer subscale total score of the Functional Assessment of Cancer Therapy (FACT) questionnaire. No differences in outcomes were observed between patients treated with olaparib and those receiving placebo.

OPINION Study

OPINION was a non-comparative, multicenter, phase IIIb study evaluating olaparib as maintenance therapy in patients with platinum-sensitive recurrent ovarian, fallopian tube, or primary peritoneal cancer after two or more lines of platinum-based chemotherapy, who did not have a known deleterious or suspected deleterious germline BRCA mutation. Patients included in the study had a response to treatment (CR or PR) following completion of platinum-based chemotherapy. A total of 279 patients were enrolled in this study and received olaparib treatment until disease progression or unacceptable toxicity. Central laboratory testing confirmed the absence of germline BRCA mutations in 90.7% of patients, while somatic BRCA mutations were detected in 9.7%.

The primary endpoint was investigator-assessed PFS according to modified RECIST version 1.1 criteria. Secondary endpoints included OS.

Olaparib demonstrated clinical activity as maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer without germline BRCA mutations. At the time of final analysis of OS (data cutoff date: September 17, 2021), maturity of OS data was 52.3%.

Summary results of the OPINION study for the primary endpoint PFS and secondary endpoint OS in patients with platinum-sensitive recurrent ovarian cancer without germline BRCA mutation are presented in Table 6.

Table 6

Summary of key objective outcomes from the OPINION study in patients with platinum-sensitive recurrent ovarian cancer without germline BRCA mutation

a Calculated using the Kaplan–Meier method.

Confidence intervals for median PFS were derived using the Brookmeyer–Crowley method.

2 q.d. – twice daily; PFS – progression-free survival; OS – overall survival; CI – confidence interval.

First-line maintenance therapy of HRD-positive advanced ovarian cancer

Study PAOLA-1

PAOLA-1 was a randomized, double-blind, placebo-controlled, multicenter, phase III trial comparing the efficacy and safety of the medicinal product Lynparza (300 mg [2 tablets of 150 mg] twice daily) in combination with bevacizumab (15 mg/kg body weight administered once every 3 weeks as an intravenous infusion) versus placebo plus bevacizumab as maintenance therapy in patients with advanced (stage III and IV according to the International Federation of Gynecology and Obstetrics [FIGO] classification) high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer following first-line platinum-based chemotherapy in combination with bevacizumab. Bevacizumab treatment continued for up to 15 months / 22 cycles in total, including the period when it was administered concomitantly with chemotherapy and as maintenance therapy.

A total of 806 patients were randomized (randomization ratio 2:1: 537 – olaparib/bevacizumab; 269 – placebo/bevacizumab), who had no evidence of disease after complete surgical resection or who achieved a complete response (CR) or partial response (PR) to treatment after completion of first-line platinum-based chemotherapy with bevacizumab. Patients had completed a minimum of 4 and a maximum of 9 cycles of treatment, with the majority (63%) receiving 6 cycles of platinum-based chemotherapy with or without taxanes, including at least 2 cycles of bevacizumab in combination with the last 3 chemotherapy cycles. The median number of bevacizumab cycles prior to randomization was 5.

Patients were stratified by first-line therapy outcomes (timing and results of cytoreductive surgery and response to platinum-based chemotherapy) and tBRCA mutation status, determined by prospective analysis at a local laboratory. Patients continued receiving bevacizumab as maintenance therapy and initiated treatment with the medicinal product Lynparza no earlier than 3 weeks and no later than 9 weeks after the last dose of chemotherapy. Treatment with Lynparza continued until disease progression, unacceptable toxicity, or for up to 2 years. Patients who, in the opinion of the treating physician, could derive additional benefit, were allowed to continue treatment beyond 2 years.

Demographic data and baseline characteristics were generally balanced between the two treatment groups: in the overall intention-to-treat (ITT) population and in biomarker-defined subgroups for tBRCA mutation status (determined prospectively and retrospectively), genomic instability score (GIS), and HRD status (defined in this study using a combination of two biomarkers). The median age of patients in both groups was 61 years. The majority of patients in both groups had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (70%). Ovarian cancer was the primary tumor in 86% of patients. The most common histological type was serous carcinoma (96%). Endometrioid carcinoma was observed in 2% of patients. Most patients (63%) had FIGO stage IIIC disease. All patients received first-line platinum-based chemotherapy with bevacizumab. Patients were not restricted by surgical outcome: 63% underwent complete primary or interval cytoreduction, while 37% had macroscopic residual disease. A tBRCA mutation was detected in 30% of patients in both groups at screening. Demographic and baseline characteristics in biomarker-defined subgroups were comparable to those in the ITT population. In the HRD-positive subgroup, 65% of patients had complete cytoreduction and 35% had macroscopic residual disease. In the overall study population at screening, tBRCA mutations (pathogenic/likely pathogenic) were identified in 30% of patients in both groups by local laboratory testing, and the tBRCA mutation status was unknown in 4% of patients. Retrospective analysis of available clinical samples was performed in 97% of patients to confirm tBRCA mutation status and to assess genomic instability score as described above. Among patients without tBRCA mutations (19% of the total population), 29% had a positive GIS, predefined in this study as a composite score ≥ 42. Combining tBRCA mutation status and positive GIS, patients with HRD-positive, HRD-negative, and HRD-unknown tumor status accounted for 48%, 34%, and 18% of the overall population, respectively.

The primary endpoint was progression-free survival (PFS), defined as the time from randomization to disease progression, as assessed by the investigator using modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, or death. Secondary efficacy endpoints included time from randomization to second progression or death (PFS2), overall survival (OS), time from randomization to treatment discontinuation or death (TDT), time from randomization to first subsequent anti-cancer therapy or death (TFST), and health-related quality of life (HRQoL). Tumor assessments using RECIST 1.1 were performed at baseline, every 24 weeks (CT/MRI at 12 weeks if progression occurred clinically or based on CA-125 levels), for up to 42 months or until radiologically confirmed objective disease progression.

The study met its primary objective in the ITT population, demonstrating a statistically significant improvement in investigator-assessed PFS with olaparib/bevacizumab compared to placebo/bevacizumab (HR 0.59, 95% CI 0.49–0.72, p-value < 0.0001; median 22.1 months for olaparib/bevacizumab vs. 16.6 months for placebo/bevacizumab). Results were consistent with the PFS analysis assessed by blinded independent central review (BICR). However, patients identified as "positive" by biomarkers (tBRCA m, GIS-positive, HRD-positive defined as tBRCA m and/or GIS-positive) derived the greatest benefit from treatment.

The final PFS2 analysis (data cutoff date March 22, 2020; 53% maturity) in the overall population was statistically significant (HR 0.78; 95% CI 0.64–0.95, p = 0.0125) with a median of 36.5 months for olaparib/bevacizumab versus 32.6 months for placebo/bevacizumab.

At the time of final OS analysis (data cutoff date March 22, 2022), a numerical improvement in OS was observed in patients with HRD-positive status (tBRCA m and/or GIS-positive) in the olaparib/bevacizumab group compared to the placebo/bevacizumab group (see Table 7).

In the randomized subgroup with tBRCA m (241 out of 806 patients), the median PFS for patients receiving olaparib/bevacizumab was 37.2 months compared to 22.0 months in the placebo/bevacizumab group (HR = 0.34; 95% CI 0.23; 0.51).

At the time of final OS analysis (data cutoff date March 22, 2022), a numerical reduction in the risk of death was observed in the tBRCA m subgroup receiving olaparib/bevacizumab compared to placebo/bevacizumab (HR 0.63; 95% CI 0.41–0.97).

Efficacy results in other biomarker-defined subgroups based on retrospective tumor sample analysis are presented in Table 7.

Table 7

Summary of efficacy outcomes in patients with homologous recombination deficiency (HRD)-positive advanced ovarian cancer defined by tBRCAm and/or GIS in the PAOLA-1 study

* Pre-specified subgroup.

a Based on Kaplan-Meier estimates, the proportions of patients without disease progression at 12 and 24 months were 89% and 66% in the olaparib/bevacizumab group and 71% and 29% in the placebo/bevacizumab group.

b If the value is < 1, olaparib is more effective. Analysis was performed using a Cox proportional hazards model stratified by response to first-line chemotherapy at screening and by tBRCA status as determined in the laboratory.

c tBRCA mutation status as assessed by Myriad.

d HRD-positive status, excluding tBRCAm, was defined as a genomic instability score (GIS) assessed by Myriad > 42 (pre-specified thresholds).

CI – confidence interval; HR – hazard ratio; NR – not reached.

Adjuvant treatment of early-stage, high-risk breast cancer with germline BRCA mutations

OlympiA trial

The efficacy and safety of olaparib as adjuvant therapy in patients with germline BRCA1/2 mutations and HER2-negative early-stage breast cancer at high risk, who had completed definitive local treatment and neoadjuvant or adjuvant chemotherapy, were evaluated in a multicenter, randomized, double-blind, placebo-controlled, phase III trial with parallel groups (OlympiA). Patients were required to have completed at least 6 cycles of neoadjuvant or adjuvant chemotherapy consisting of anthracyclines, taxanes, or both drug classes. Prior treatment with platinum agents for a previous cancer (e.g., ovarian cancer) or adjuvant or neoadjuvant therapy for breast cancer was permitted. Patients with early-stage, high-risk breast cancer were defined as follows:

• Patients who received prior neoadjuvant chemotherapy: patients with triple-negative breast cancer (TNBC) or hormone receptor-positive breast cancer who had residual invasive disease in the breast and/or lymph nodes (incomplete pathological response) at the time of surgery. Additionally, patients with hormone receptor-positive breast cancer were required to have a CPS&EG score ≥ 3, calculated based on clinical stage before treatment and pathological stage after treatment (CPS), estrogen receptor (ER) status, and histological grade, as shown in Table 8.

Table 8

Criteria for early breast cancer stage, receptor status, and differentiation grade for inclusion in the study*

* Patients with hormone receptor-positive breast cancer were required to have a total score ≥ 3.

• Patients who had received prior adjuvant chemotherapy: patients with triple-negative breast cancer (TNBC) were required to have lymph node involvement or, if no lymph node involvement, a primary tumor size ≥ 2 cm; hormone receptor-positive, HER2-negative patients were required to have ≥ 4 lymph nodes involved, confirmed by pathological examination.

Patients were randomized (1:1) to receive either olaparib 300 mg (2 tablets of 150 mg) twice daily (n = 921) or placebo (n = 915). Patients were stratified by hormone receptor (HR) status (HR-positive/HER2-negative vs. TNBC), prior neoadjuvant vs. adjuvant chemotherapy, and prior use of platinum-containing agents for the treatment of existing breast cancer (yes vs. no). Treatment continued for up to 1 year or until disease recurrence or unacceptable toxicity occurred. Patients with HR-positive tumors also received endocrine therapy.

The primary endpoint was invasive disease-free survival (iDFS), defined as the time from randomization to the date of first recurrence, where recurrence was defined as invasive locoregional recurrence, distant recurrence, invasive contralateral breast cancer, new primary cancer, or death from any cause. Secondary endpoints included overall survival (OS), distant metastasis-free survival (DMFS, defined as the time from randomization to confirmation of first distant recurrence of breast cancer), incidence of new primary contralateral breast cancer (invasive and non-invasive), new primary ovarian cancer, new primary fallopian tube cancer, new primary peritoneal cancer, and patient-reported treatment outcomes based on the FACIT-Fatigue and EORTC QLQ-C30 questionnaires.

Centralized testing for germline BRCA gene mutations, performed by Myriad or at a local laboratory if available, was used to determine patient eligibility for the study. Patients enrolled based on locally conducted germline BRCA mutation testing provided a sample for retrospective confirmatory testing. Of the 1836 patients enrolled in the OlympiA study, germline BRCA mutations were centrally confirmed in 1623 patients. Confirmatory testing was performed prospectively or retrospectively.

Demographic and baseline characteristics were well balanced between the two treatment groups. The median age of patients was 42 years. Of all patients, 67% were of Caucasian race, 29% were of Asian race, and 2.6% were of Black race. Two patients (0.2%) in the olaparib group and four patients (0.4%) in the placebo group were male. 61% of patients were premenopausal. ECOG performance status was 0 in 89% and 1 in 11%. 82% of patients had TNBC, and 18% had HR-positive disease. Fifty percent (50%) of patients received prior neoadjuvant chemotherapy and 50% received adjuvant chemotherapy. 94% of patients received anthracycline- and taxane-based chemotherapy. 26% of patients received prior platinum-based therapy for breast cancer. In the olaparib and placebo groups, 87% and 92% of patients with HR-positive disease, respectively, received concomitant endocrine therapy. Overall, 89.5% of patients with HR-positive disease received endocrine therapy, which included letrozole (23.7%), tamoxifen (40.9%), anastrozole (17.2%), or exemestane (14.8%).

The study met its primary endpoint, demonstrating a statistically significant improvement in iDFS in the olaparib group compared to the placebo group. iDFS events were confirmed in 284 patients, representing 12% of patients in the olaparib group (distant – 8%, local/regional – 1.4%, invasive contralateral breast cancer – 0.9%, second primary malignancies unrelated to breast – 1.2%, death – 0.2%) and 20% in the placebo group (distant – 13%, local/regional – 2.7%, invasive contralateral breast cancer – 1.3%, second primary malignancies unrelated to breast – 2.3%, death – 0%). A statistically significant improvement in DMFS was also reported in the olaparib group compared to placebo. At the next pre-planned analysis of OS, a statistically significant improvement in OS was observed in the olaparib group compared to placebo.

Efficacy results in the full analysis set (FAS) population are presented in Table 9.

Table 9

Efficacy results of adjuvant therapy in patients with early-stage breast cancer and germline BRCA gene mutations, OlympiA trial

a Based on a stratified proportional hazards model, < 1 indicates a lower risk for olaparib compared to placebo.

b P-value from stratified log-rank test.

c Percentages calculated using the Kaplan-Meier method.

2 BID – twice daily; CI – confidence interval; MFS – metastasis-free survival; iDFS – invasive disease-free survival; KM – Kaplan-Meier method; OS – overall survival.

HER2-negative metastatic breast cancer with germline BRCA1/2 gene mutation (gBRCA1/2)

OlympiAD (study D0819C00003)

The safety and efficacy of olaparib in patients with HER2-negative metastatic breast cancer and germline BRCA1/2 gene mutations were evaluated in a randomized, open-label, controlled Phase III trial (OlympiAD). In this study, 302 patients with documented pathogenic or suspected pathogenic germline BRCA gene mutations were randomized in a 2:1 ratio to receive either Lynparza (300 mg [2 tablets of 150 mg] twice daily) or physician’s choice of chemotherapy (capecitabine 42%, eribulin 35%, or vinorelbine 17%) until disease progression or unacceptable toxicity. Patients with BRCA1/2 mutations were identified through germline mutation testing in blood at a local laboratory or at the central laboratory of Myriad Genetics. Patients were stratified by prior chemotherapy for metastatic breast cancer (yes/no), hormone receptor-positive versus triple-negative breast cancer (TNBC), and prior platinum-based therapy for breast cancer (yes/no). The primary endpoint was progression-free survival (PFS), assessed by blinded independent central review (BICR) using RECIST version 1.1. Secondary endpoints included PFS2, overall survival (OS), objective response rate (ORR), and health-related quality of life (HRQoL).

Patients were required to have received prior treatment with an anthracycline, unless contraindicated, and a taxane in the (neo)adjuvant or metastatic setting. Patients with hormone receptor-positive (ER- and/or PgR-positive) tumors were required to have received at least one line of endocrine therapy (adjuvant or for metastatic disease) with disease progression thereafter, or had disease considered by their physician as not amenable to endocrine therapy. Prior platinum-based therapy was allowed for metastatic disease provided there was no progression during platinum therapy, or in the (neo)adjuvant setting provided the last dose was administered at least 12 months prior to randomization. Prior treatment with a PARP inhibitor, including olaparib, was prohibited.

Demographic and baseline characteristics were generally balanced between the olaparib and control treatment groups (see Table 10).

Table 10

Demographic and baseline patient characteristics in the OlympiAD study

In the groups receiving the investigational medicinal product and the comparator medicinal product, 0.5 % and 8 % of patients, respectively, received subsequent therapy with a PARP inhibitor. A total of 29 % and 42 % of patients, respectively, received subsequent therapy with platinum-based agents.

In patients treated with olaparib, as compared to those receiving the comparator medicinal product, a statistically significant improvement in PFS, the primary efficacy endpoint, was demonstrated (see Table 11).

Table 11

Summary of efficacy results in patients with HER2-negative metastatic breast cancer and germline BRCA1/2 mutations in the OlympiAD study

CI – confidence interval; HR – hazard ratio; HR+ – hormone receptor-positive cancer; ORR – objective response rate; OS – overall survival; PFS – progression-free survival; PFS2 – time to second progression or death; TNBC – triple-negative breast cancer.

a According to stratified log-rank test.

b Retrospective analysis.

c Median follow-up time in censored cases was 25.3 months in the olaparib group and 26.3 months in the control drug group.

d Confirmed responses (based on blinded independent central review or BICR) were defined as complete response (CR) or partial response (PR), confirmed by imaging at least 4 weeks after the visit at which the response was first observed. Complete response was observed in 8% of patients with measurable disease in the olaparib group and in 1.5% of patients in the control drug group. Partial response was observed in 74/167 (44%) patients in the olaparib group and in 14/66 (21%) patients in the chemotherapy group. In the subgroup of patients with TNBC, confirmed ORR was 48% (41/86) in the olaparib group and 12% (4/33) in the control drug group. In the subgroup of patients with hormone receptor-positive cancer, confirmed ORR was 57% (46/81) in the olaparib group and 33% (11/33) in the control drug group.

Results across all predefined patient subgroups were consistent. Subgroup analyses showed improved PFS in patients receiving olaparib compared to those receiving the control drug, both in the TNBC subgroup (hazard ratio 0.43; 95% CI 0.29–0.63, n = 152) and in the hormone receptor-positive cancer subgroup (hazard ratio 0.82; 95% CI 0.55–1.26, n = 150).

In a retrospective analysis of the subgroup of patients who did not show disease progression after non-platinum chemotherapy, median PFS was 8.3 months (95% CI 3.1–16.7) in the olaparib group (n = 22) and 2.8 months (95% CI 1.4–4.2) in the chemotherapy group (n = 16). The hazard ratio was 0.54 (95% CI 0.24–1.23). However, the number of patients is too limited to draw reliable conclusions about the efficacy of the drug in this patient subgroup.

Seven male patients were randomized (5 received olaparib and 2 received the control drug). At the time of PFS analysis, one patient in the olaparib group had confirmed partial response lasting 9.7 months. No confirmed responses were observed in the control drug group.

OS analysis in patients who had not previously received chemotherapy for metastatic breast cancer showed a more favorable effect in these patients: hazard ratio (HR) was 0.45 (95% CI 0.27–0.77), whereas after prior lines of therapy, the HR was greater than 1.

Maintenance treatment following first-line therapy in patients with metastatic pancreatic adenocarcinoma and germline BRCA mutation

POLO Study

The safety and efficacy of olaparib as maintenance therapy were evaluated in a randomized (3:2), double-blind, placebo-controlled, multicenter study involving 154 patients with metastatic pancreatic adenocarcinoma and germline BRCA1/2 gene mutation. Patients received either Lynparza 300 mg (two 150 mg tablets) twice daily (n = 92) or placebo (n = 62) until disease progression or unacceptable toxicity. Patients’ disease should not have progressed during first-line platinum-based chemotherapy, and patients had to complete at least 16 weeks of continuous platinum-based therapy, which could be discontinued at any time after initiation due to unacceptable toxicity, while continuing the remaining drugs according to the planned regimen or until unacceptable toxicity to other components. Patients who tolerated platinum-based chemotherapy until disease progression were not eligible for inclusion in this study. Maintenance therapy was initiated 4–8 weeks after the last dose of first-line chemotherapy components, in the absence of disease progression and provided all toxic effects from prior anti-tumor therapy had resolved to CTCAE grade 1, except for alopecia, grade 3 peripheral neuropathy, and hemoglobin level ≥ 9 g/dL.

Thirty-one percent (31%) of patients with germline BRCA1/2 gene mutation were identified based on prior testing at a local laboratory, and 69% were identified by testing at a central laboratory. In the olaparib group, 32% of patients had germline BRCA1 mutation, 64% had germline BRCA2 mutation, and 1% had germline mutations in both BRCA1 and BRCA2. In the placebo group, 26% of patients had germline BRCA1 mutation, 73% had germline BRCA2 mutation, and no patient had germline mutations in both BRCA1 and BRCA2. The BRCA mutation status of all patients identified by prior local laboratory testing was confirmed, in individual cases by submission of documentation, through central laboratory testing. Ninety-eight percent (98%) of patients had a deleterious mutation, and 2% had a suspected deleterious mutation. Large rearrangements in BRCA1/2 genes were detected in 5.2% (8/154) of randomized patients.

Demographic data and baseline characteristics were generally comparable between the olaparib and placebo treatment groups. Median age in both groups was 57 years; 30% of patients in the olaparib group were aged ≥ 65 years compared to 20% in the placebo group. Fifty-eight percent (58%) of patients in the olaparib group and 50% in the placebo group were male. In the olaparib group, 89% of patients were of Caucasian race and 11% were of non-Caucasian race; in the placebo group, 95% were Caucasian and 5% non-Caucasian. The majority of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (71% in the olaparib group and 61% in the placebo group). Overall, metastases prior to chemotherapy were located in the liver (72%), lungs (10%), and other sites (50%). Median time from initial diagnosis to randomization was 6.9 months in both groups (range 3.6 to 38.4 months).

Overall, 75% of patients received FOLFIRINOX with a median of 9 cycles (range 4–61), 8% received FOLFOX or XELOX, 4% received GEMOX, and 3% received gemcitabine plus cisplatin; the remaining 10% received other chemotherapy regimens. Duration of first-line chemotherapy for metastatic disease was 4–6 months, >6 to <12 months, and ≥12 months in 77%, 19%, and 4% of patients in the olaparib group and in 80%, 17%, and 3% in the placebo group, respectively. The interval from the last dose of first-line chemotherapy component(s) to initiation of study treatment was approximately 1 month in both groups. As best response to first-line chemotherapy, 7% of patients in the olaparib group and 5% in the placebo group achieved complete response, 44% in the olaparib group and 44% in the placebo group achieved partial response, and 49% in the olaparib group and 50% in the placebo group had stable disease. At randomization, measurable disease was recorded in 85% and 84% of patients in the olaparib and placebo groups, respectively. Median time from initiation of first-line platinum-based chemotherapy to randomization was 5.7 months (range 3.4 to 33.4 months).

At the time of PFS analysis, 33% of patients in the olaparib group and 13% in the placebo group were still receiving study treatment. Forty-nine percent (49%) of patients in the olaparib group and 74% in the placebo group received subsequent therapy. Forty-two percent (42%) of patients in the olaparib group and 55% in the placebo group received platinum-based agents as subsequent therapy. One percent (1%) of patients in the olaparib group and 15% in the placebo group received a PARP inhibitor as subsequent therapy. Among 33 (36%) and 28 (45%) patients in the olaparib and placebo groups who received first subsequent platinum-based therapy, stable disease was observed in 8 and 6 patients, respectively, while response to treatment was observed in 1 and 2 patients, respectively.

The primary endpoint was progression-free survival (PFS), defined as the time from randomization to disease progression as assessed by the investigator using modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, or death. Secondary efficacy endpoints included overall survival (OS), time from randomization to second progression or death (PFS2), time from randomization to first subsequent anti-cancer therapy or death (TFST), objective response rate (ORR), duration of response (DoR), response rate, time to response, and health-related quality of life (HRQoL).

The study demonstrated a statistically significant improvement in PFS with olaparib compared to placebo (Table 12). PFS assessment by blinded independent central review (BICR) was consistent with investigator assessment.

At the time of final OS analysis, the percentage of patients remaining alive and under follow-up was 28% in the olaparib group and 18% in the placebo group.

Table 12

Efficacy results in patients with metastatic pancreatic adenocarcinoma and germline BRCA mutation in the POLO study

a According to Kaplan-Meier estimates, the proportion of patients who were alive and had not experienced disease progression at 12 and 24 months was 34% and 22% in the olaparib group, compared with 15% and 10% in the placebo group.

b For PFS, the median duration of follow-up for censored cases was 9.1 months in the olaparib group and 3.8 months in the placebo group.

c If the value is < 1, olaparib is more effective.

d The analysis was performed using the stratified log-rank test.

e For OS, the median duration of further follow-up for censored patients was 31.3 months in the olaparib group and 23.9 months in the placebo group.

2 r/d – twice daily; CI – confidence interval; HR – hazard ratio; OS – overall survival; PFS – progression-free survival.

Metastatic castration-resistant prostate cancer with BRCA1/2 gene mutations

Study PROfound

The safety and efficacy of olaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) were evaluated in a randomized, open-label, multicenter Phase III trial assessing the efficacy of Lynparza versus a comparator agent in patients receiving a new hormonal agent (NHA [enzalutamide or abiraterone acetate]) as chosen by the investigator.

Patients had experienced disease progression following prior treatment with an NHA for metastatic prostate cancer and/or CRPC. To be included in Cohort A, patients were required to have deleterious or suspected deleterious mutations in the BRCA1 or BRCA2 genes. Patients with ATM mutations were also randomized into Cohort A, but a positive benefit-risk balance could not be demonstrated in this patient subpopulation. Patients with mutations in other genes were randomized into Cohort B.

In this study, 387 patients were randomized in a 2:1 ratio to receive either olaparib (300 mg [2 tablets of 150 mg] twice daily) or the comparator agent. Cohort A included 245 patients (162 received olaparib and 83 received the comparator), and Cohort B included 142 patients (94 received olaparib and 48 received the comparator). Patients were stratified by prior taxane use and presence of measurable disease. Treatment continued until disease progression. Patients randomized to the comparator arm were allowed to cross over to olaparib upon radiologically confirmed disease progression, as assessed by blinded independent central review (BICR). Patients with BRCA1 and BRCA2 mutations identified in tumor tissue were enrolled based on prospective testing at a central laboratory, except for 3 patients enrolled based on local laboratory testing. Among the 160 patients with BRCA1 or BRCA2 mutations in the PROfound study, 114 underwent retrospective analysis to determine whether the BRCA1/2 mutation was germline or somatic. Of these, 63 BRCA1/2 mutations were detected in germline blood samples and thus classified as germline. In the remaining patients (51), no tumor BRCA1/2 mutations were identifiable in germline blood samples, and thus the mutations were classified as somatic. The nature of the mutations (somatic vs. germline) remained unknown in the remaining 46 patients.

Demographic and baseline characteristics were generally well balanced between the BRCA1/2-mutated patients receiving olaparib or the comparator agent. Median age was 68 years and 67 years in the olaparib and comparator groups, respectively. Prior therapies in the olaparib group included: 71% taxanes, 41% enzalutamide, 37% abiraterone acetate, and 20% both enzalutamide and abiraterone acetate. Prior therapies in the comparator group included: 60% taxanes, 50% enzalutamide, 36% abiraterone acetate, and 14% both enzalutamide and abiraterone acetate. Fifty-eight percent (58%) of patients in the olaparib group and 55% in the comparator group had measurable disease at study entry. The proportions of patients with bone, lymph node, visceral, and liver metastases were 89%, 62%, 23%, and 12% in the olaparib group, and 86%, 71%, 16%, and 17% in the comparator group, respectively. The majority of patients in both treatment groups had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (93%). Baseline pain levels (worst pain assessed by the Brief Pain Inventory–Short Form [BPI-SF]) were 0 to < 2 (52%), 2–3 (10%), or > 3 (34%) in the olaparib group, and 0 to < 2 (45%), 2–3 (7%), or > 3 (45%) in the comparator group. Median baseline PSA was 57.48 µg/L in the olaparib group and 103.95 µg/L in the comparator group.

The primary endpoint of the study was radiographic progression-free survival (rPFS) in Cohort A, assessed by blinded independent central review (BICR) using RECIST version 1.1 (soft tissue) and Prostate Cancer Working Group 3 (PCWG3) criteria (bone). Key secondary endpoints included confirmed objective response rate (ORR) as assessed by BICR, rPFS by BICR, time to pain progression (TTPP), and overall survival (OS).

The study demonstrated statistically significant improvements in rPFS as assessed by BICR and final OS for olaparib compared to the comparator agent in Cohort A.

Results in patients with BRCA1/2 gene mutations are presented in Table 13. A statistically significant improvement in rPFS by BICR assessment was observed for olaparib compared to investigator-chosen NHA in the BRCA1/2 mutation patient group. The final OS analysis showed nominally statistically significant improvement in OS for patients with BRCA1/2 mutations randomized to Lynparza compared to those receiving the comparator agent.

Table 13

Summary of efficacy results in patients with mCRPC and BRCA1/2 gene mutations from the PROfound study

a Without control for multiplicity.

b rPFS 71% data maturity.

c HR and CI were calculated using the Cox proportional hazards model, which included treatment, factor, and treatment-by-factor interaction terms.

2 q.d. – twice daily; BICR – blinded independent central review; CI – confidence interval; HR – hazard ratio; NE – not estimable; NHA – new hormonal agent; ORR – objective response rate; OS – overall survival; rPFS – radiographic progression-free survival

First-line therapy for mCRPC

PROpel Study

The safety and efficacy of olaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) were evaluated in a randomized, double-blind, placebo-controlled, multicenter Phase III trial assessing the efficacy of the medicinal product Lynparza (300 mg [2 tablets of 150 mg] twice daily) in combination with abiraterone (1000 mg [2 tablets of 500 mg] once daily) versus placebo in combination with abiraterone. Patients in both groups also received prednisone or prednisolone at a dose of 5 mg twice daily.

In this study, 796 patients were randomized in a 1:1 ratio (399 received olaparib/abiraterone, 397 received placebo/abiraterone). Study participants had histologically confirmed adenocarcinoma of the prostate and metastatic status defined by the presence of at least one metastatic lesion confirmed by bone scan or CT/MRI. Patients had not received chemotherapy or treatment with NHA for mCRPC. Prior NHA treatment (excluding abiraterone) for mCRPC without progression (biochemical/clinical/radiological) during therapy was allowed, provided it was discontinued at least 12 months prior to randomization. First-generation antiandrogen agents (e.g., bicalutamide, nilutamide, flutamide) were permitted if a 4-week washout period was observed. Docetaxel treatment was allowed during neoadjuvant/adjuvant therapy for localized prostate cancer and in the metastatic hormone-sensitive prostate cancer (mHSPC) setting, provided there was no evidence of disease progression during or immediately after such treatment. All patients received a gonadotropin-releasing hormone (GnRH) analogue or had undergone prior bilateral orchidectomy. Patients were stratified by type of metastases (bone-only, visceral, or other) and prior docetaxel treatment in the mHSPC setting (yes or no). Treatment continued until radiologically confirmed disease progression or occurrence of unacceptable toxic effects.

Demographic data and baseline characteristics were generally balanced between the two study groups. The median age in both groups was 69 years, with the majority (71%) of patients aged >65 years. Overall, 189 patients (24%) had received docetaxel therapy in the mHSPC setting. A total of 434 (55%) patients had bone metastases (bone metastases without distant involvement in other sites), 105 (13%) had visceral metastases (distant metastases in soft tissues or organs, e.g., liver or lungs), and 257 (32%) had metastases at other sites (including, in particular, patients with bone metastases and distant lymph nodes, or patients with distant lymph nodes only).

The majority of patients in both groups (70%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0. In the olaparib group, symptomatic disease was reported in 103 (25.8%) patients, compared to 80 (20.2%) in the placebo group. Symptomatic patients had a score of ≥4 on item 3 of the Brief Pain Inventory–Short Form (BPI-SF) and/or were receiving opioid analgesics prior to treatment initiation.

Biomarker status was not an eligibility criterion for inclusion in the study. HRR gene mutation status was retrospectively assessed using cell-free DNA (cfDNA) analysis and tumor tissue testing to evaluate treatment effect consistency in the full analysis set (FAS). Among all patients who underwent cfDNA and tumor tissue testing, 198 and 118 patients, respectively, had HRR gene mutations. The distribution of patients with HRR gene mutations was well balanced between the two groups.

The primary endpoint of the study was radiographic progression-free survival (rPFS), assessed by the investigator using modified Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, and Prostate Cancer Working Group 3 (PCWG-3) criteria (for bone). The key secondary efficacy endpoint was overall survival (OS). Additional secondary efficacy endpoints included time from randomization to second progression or death (PFS2), time from randomization to first subsequent therapy or death (TST), and health-related quality of life (HRQoL).

The study met its primary endpoint, demonstrating a statistically significant improvement (investigator-assessed) in the risk of radiologically confirmed disease progression or death in the olaparib/abiraterone group compared to the placebo/abiraterone group (HR 0.66; 95% CI 0.54, 0.81; p < 0.0001; median rPFS 24.8 months in the olaparib/abiraterone group versus 16.6 months in the placebo/abiraterone group). Investigator-assessed rPFS was independently confirmed by blinded independent central review (BICR). The sensitivity analysis of BICR-assessed rPFS was consistent with investigator assessment (HR 0.61; 95% CI 0.49, 0.74; p < 0.0001; median rPFS 27.6 months in the olaparib/abiraterone group versus 16.4 months in the placebo/abiraterone group).

Results across all predefined subgroups, including patients who previously received or did not receive taxanes in the mHSPC setting, patients with different metastatic involvement at baseline (bone-only, visceral, or other metastases), and patients with or without HRR gene mutations, were consistent with the overall results favoring the olaparib/abiraterone group over placebo/abiraterone.

Efficacy results are presented in Table 14.

Table 14

Summary of key efficacy findings from the PROpel study in patients with mCRPC

a HR and p-values were calculated using the Cox proportional hazards model, adjusted for variables selected in the primary combination strategy: presence of metastases, prior treatment with docetaxel in the mCRPC setting. Efron's method was used to handle tied events. HR < 1 favors the combination of olaparib 300 mg twice daily + abiraterone 1000 mg once daily.

b Two-sided p-values were calculated using the log-rank test, stratified by the same variables selected in the primary combination strategy.

c Calculated using the Kaplan-Meier method.

Table 15

Analysis of rPFS in subgroups (investigator assessment) — PROpel study (data cutoff date: July 30, 2021)

a The combined subgroups were defined by the ctDNA analysis groups and tumor tissue testing.

b The analysis was performed using the Cox proportional hazards model, including terms for treatment group, subgroup factor, and treatment efficacy depending on subgroup. The confidence interval was calculated using the profile likelihood method. If HR < 1, olaparib 300 mg twice daily is considered more effective.

Subgroup analyses were performed using a Cox proportional hazards model that included terms for assigned treatment, factor, and treatment efficacy depending on the factor. If the hazard ratio < 1, this indicates a lower risk of progression with olaparib treatment.

* Except for patients without baseline assessment. CI — confidence interval; ECOG — Eastern Cooperative Oncology Group; mCRPC — metastatic castration-resistant prostate cancer; NR — not estimable; PSA — prostate-specific antigen.

Pediatric population

The European Medicines Agency has waived the obligation to submit results of clinical trials with the medicinal product Lynparza in all pediatric subpopulations for ovarian cancer (except for rhabdomyosarcoma and germ cell tumors) (for information on use in children, see section "Children").

Pharmacokinetics

The pharmacokinetics of olaparib in the tablet formulation at a dose of 300 mg is characterized by a plasma clearance of approximately 7 L/h, a volume of distribution of approximately 158 L, and a terminal half-life of 15 hours. After repeated dosing, the accumulation ratio for AUC was 1.8, and pharmacokinetics was somewhat time-dependent.

Absorption

After oral administration in tablet form (2 tablets of 150 mg), olaparib is rapidly absorbed. The median time to reach peak plasma concentration after administration is typically 1.5 hours.

When olaparib was administered with food, its absorption was delayed (tmax increased by 2.5 hours and Cmax decreased by approximately 21%), but the extent of absorption was not significantly altered (AUC increased by 8%). Therefore, the medicinal product Lynparza can be taken with or without food (see section "Special instructions for use").

Distribution

The degree of olaparib binding to plasma proteins in vitro is approximately 82% at a concentration of 10 µg/mL, which is close to Cmax.

The extent of olaparib binding to human plasma proteins in vitro was dose-dependent. The bound fraction was approximately 91% at a concentration of 1 µg/mL, decreasing to 82% at 10 µg/mL and to 70% at 40 µg/mL. In solutions of purified proteins, the fraction of olaparib bound to albumin was approximately 56% and independent of olaparib concentrations. Using the same assay, the fraction of olaparib bound to alpha-1-acid glycoprotein was determined to be 29% at a concentration of 10 µg/mL and decreased at higher concentrations.

Biotransformation

In vitro, CYP3A4/5 were shown to be the primary enzymes responsible for olaparib metabolism (see section "Interaction with other medicinal products and other forms of interaction").

After oral administration of radiolabeled olaparib (14C) to patients, unchanged olaparib accounted for the majority of circulating radioactivity in plasma (70%) and was the main component present in both urine and feces (15% and 6% of dose, respectively). Olaparib undergoes extensive metabolism. Oxidation reactions played a major role, leading to a number of metabolites that subsequently underwent glucuronidation or sulfation. Up to 20, 37, and 20 metabolites were detected in plasma, urine, and feces, respectively, most of which accounted for <1% of the administered dose. The main circulating components were the opened-ring piperazine-3-ol and two mono-oxidized metabolites (each accounting for approximately 10%). One of the mono-oxidized metabolites was also the main metabolite present in excreta (accounting for 6% and 5% of radioactivity in urine and feces, respectively).

In vitro, olaparib weakly inhibited or did not inhibit UGT1A4, UGT1A9, UGT2B7, or CYP isoforms 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1, and is not expected to cause any clinically significant time-dependent inhibition of these CYP enzymes. Olaparib inhibited UGT1A1 activity in vitro, but physiologically based pharmacokinetic modeling results suggest that this effect is not clinically relevant. In vitro, olaparib is a substrate of the efflux transporter P-glycoprotein, but this property is unlikely to be clinically significant (see section "Interaction with other medicinal products and other forms of interaction").

In vitro data also indicate that olaparib is not a substrate of OATP1B1, OATP1B3, OCT1, BCRP, or MRP2, and is not an inhibitor of OATP1B3, OAT1, or MRP2.

Elimination

After a single dose of radiolabeled olaparib (14C), approximately 86% of the administered radioactive dose was recovered within the 7-day sample collection period, with approximately 44% excreted in urine and 42% in feces. The drug was primarily eliminated as metabolites.

Special patient populations

In population pharmacokinetic analyses, patient age, sex, body weight, tumor location, or race (including patients of Caucasian descent and Japanese patients) were not significant covariates.

Renal impairment

In patients with mild renal impairment (creatinine clearance 51–80 mL/min), AUC increased by 24% and Cmax by 15% compared to patients with normal renal function. Dose adjustment of Lynparza is not required in patients with mild renal impairment.

In patients with moderate renal impairment (creatinine clearance 31–50 mL/min), AUC increased by 44% and Cmax by 26% compared to patients with normal renal function. Dose adjustment of Lynparza is recommended for patients with moderate renal impairment (see section "Dosage and administration").

There are no data available for patients with severe renal impairment or end-stage renal disease (creatinine clearance < 30 mL/min).

Hepatic impairment

Compared to patients with normal hepatic function, in patients with mild hepatic impairment (Child-Pugh class A), AUC increased by 15% and Cmax by 13%, while in patients with moderate hepatic impairment (Child-Pugh class B), AUC increased by 8% and Cmax decreased by 13%. Dose adjustment of Lynparza is not required in patients with mild or moderate hepatic impairment (see section "Dosage and administration"). There are no data available for patients with severe hepatic impairment (Child-Pugh class C).

Pediatric population

Pharmacokinetic studies of olaparib in children have not been conducted.

Clinical characteristics

Indications

Ovarian cancer

Lynparza is indicated as monotherapy for:

• maintenance treatment of adult female patients with advanced (FIGO stages III and IV) high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer with BRCA1/2 mutation (germline and/or somatic) who have responded (complete or partial response) to first-line platinum-based chemotherapy;
• maintenance treatment of adult female patients with platinum-sensitive relapsed high-grade epithelial ovarian, fallopian tube, or primary peritonean cancer who have responded (complete or partial response) to platinum-based chemotherapy.

Lynparza in combination with bevacizumab is indicated for:

• maintenance treatment of adult female patients with advanced (FIGO stages III and IV) high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who have responded (complete or partial response) to first-line platinum-based chemotherapy in combination with bevacizumab and whose cancer is associated with a positive homologous recombination deficiency (HRD) status defined by BRCA1/2 mutation and/or genomic instability (see section "Pharmacodynamics").

Breast cancer

Lynparza is indicated as:

• monotherapy or in combination with endocrine therapy for adjuvant treatment of adult patients with germline BRCA1/2 mutations who have HER2-negative early breast cancer at high risk of recurrence and who have previously received (neo)adjuvant chemotherapy (see sections "Dosage and administration" and "Pharmacodynamics");
• monotherapy for treatment of adult patients with germline BRCA1/2 mutations who have HER2-negative locally advanced or metastatic breast cancer. Patients should have previously been treated with anthracyclines and taxanes in the (neo)adjuvant or metastatic setting, unless such treatment was not suitable (see section "Pharmacodynamics").

For patients with hormone receptor-positive breast cancer, disease progression should have occurred during or after prior endocrine therapy, or endocrine therapy should be considered unsuitable.

Pancreatic adenocarcinoma

Lynparza is indicated as monotherapy for maintenance treatment of adult patients with germline BRCA1/2 mutations who have metastatic adenocarcinoma of the pancreas and whose disease has not progressed after at least 16 weeks of platinum-based first-line chemotherapy.

Prostate cancer

Lynparza is indicated as:

• monotherapy for treatment of adult patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA1/2 mutations (germline and/or somatic) who have progressed following prior treatment with a new hormonal agent;
• in combination with abiraterone and prednisone or prednisolone for treatment of adult patients with mCRPC who are not eligible for chemotherapy (see section "Pharmacodynamics").

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section "Composition".

Breastfeeding during treatment and for 1 month after the last dose (see section "Use in pregnancy and breastfeeding").

Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions

Clinical trials of olaparib in combination with other antineoplastic agents, including those causing DNA damage, indicate potentiation and prolongation of myelosuppressive toxicity of the medicinal product.

The dose of Lynparza recommended for monotherapy is not suitable when this medicinal product is used in combination with myelosuppressive antineoplastic agents.

Combinations of olaparib with vaccines or immunosuppressants have not been studied. Therefore, these medicinal products should be used concomitantly with Lynparza with caution and patients should be closely monitored.

Pharmacokinetic interactions

Effect of other medicinal products on olaparib

CYP3A4/5 are the main isoenzymes responsible for the metabolic clearance of olaparib.

A clinical study evaluating the effect of itraconazole, a known CYP3A inhibitor, showed that concomitant administration with olaparib increased the mean Cmax of olaparib by 42% (90% CI 33–52%) and the mean AUC by 170% (90% CI 144–197%). Therefore, known strong (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, boceprevir, telaprevir) or moderate (e.g. erythromycin, diltiazem, fluconazole, verapamil) inhibitors of this isoenzyme should not be used concomitantly with Lynparza (see section "Special warnings and precautions for use"). If coadministration of strong or moderate CYP3A inhibitors is necessary, the dose of Lynparza should be reduced. The dose of Lynparza should be reduced to 100 mg twice daily (equivalent to a total daily dose of 200 mg) when administered with a strong CYP3A inhibitor or to 150 mg twice daily (equivalent to a total daily dose of 300 mg) when administered with a moderate CYP3A inhibitor (see sections "Dosage and administration" and "Special warnings and precautions for use"). Grapefruit juice should also be avoided during treatment with Lynparza, as it is a CYP3A inhibitor.

In a clinical study of the effect of rifampicin, a known CYP3A inducer, concomitant administration with olaparib decreased the mean Cmax of olaparib by 71% (90% CI 76–67%) and the mean AUC by 87% (90% CI 89–84%). Therefore, concomitant use of known strong inducers of this isoenzyme (such as phenytoin, rifampicin, rifapentine, carbamazepine, nevirapine, phenobarbital, and St John's wort) with Lynparza is not recommended due to the potential for significant reduction in efficacy of Lynparza. The magnitude of the effect of moderate or strong inducers (e.g. efavirenz, rifabutin) on olaparib exposure has not been established; therefore, concomitant use of Lynparza with these medicinal products is also not recommended (see section "Special warnings and precautions for use").

Effect of olaparib on other medicinal products

Olapparib inhibits CYP3A4 in vitro and is predicted to be a weak inhibitor of CYP3A in vivo. Therefore, caution should be exercised when combining olaparib with sensitive CYP3A substrates or substrates with a narrow therapeutic index (e.g. simvastatin, cisapride, cyclosporine, ergot alkaloids, fentanyl, pimozide, sirolimus, tacrolimus, and quetiapine). When coadministered with CYP3A substrates with a narrow therapeutic index, appropriate clinical monitoring of the patient is recommended.

Induction of CYP1A2, 2B6, and 3A4 suggests that CYP2B6 is more likely to be induced to a clinically relevant extent in vitro. The potential of olaparib to induce CYP2C9, CYP2C19, and P-glycoprotein (P-gp) cannot be excluded. Thus, olaparib may cause reduced exposure of substrates of these metabolic enzymes and the transport protein when coadministered. The efficacy of some hormonal contraceptives may be reduced when coadministered with olaparib (see sections "Special warnings and precautions for use" and "Use in pregnancy and breastfeeding").

In vitro, olaparib inhibits the efflux transporter protein P-glycoprotein (half-maximal inhibitory concentration (IC50) 76 µmol/L); therefore, clinically significant interactions between olaparib and P-glycoprotein substrates (e.g. simvastatin, pravastatin, dabigatran, digoxin, and colchicine) cannot be excluded. Appropriate clinical monitoring is recommended for patients taking these types of medicinal products concomitantly.

In vitro, olaparib has been shown to inhibit BCRP, OATP1B1, OCT1, OCT2, OAT3, MATE1, and MATE2K. It cannot be excluded that olaparib may increase exposure to substrates of BCRP (e.g. methotrexate, rosuvastatin), OATP1B1 (e.g. bosentan, glyburide, repaglinide, statins, valsartan), OCT1 (e.g. metformin), OCT2 (e.g. serum creatinine), OAT3 (e.g. furosemide, methotrexate), MATE1 (e.g. metformin), and MATE2K (e.g. metformin). In particular, olaparib should be used with caution in combination with any statin.

Combination with anastrozole, letrozole, and tamoxifen

A clinical study of olaparib in combination with anastrozole, letrozole, or tamoxifen was conducted. No clinically significant interactions were observed.

Special precautions for use

Hematological toxicity

Hematological toxicity, including clinical diagnoses and/or laboratory findings indicative of anemia, neutropenia, thrombocytopenia, and lymphopenia, usually of mild or moderate severity (Grade 1 or 2 according to the Common Terminology Criteria for Adverse Events [CTCAE]), has been reported in patients treated with the medicinal product Lynparza.

Patients should not initiate treatment with Lynparza until hematotoxic effects from prior antineoplastic therapy have resolved completely (hemoglobin, platelet, and neutrophil levels must be ≤ Grade 1 according to CTCAE). A complete blood count should be performed monthly during the first 12 months of treatment and periodically thereafter to monitor for clinically significant changes in any parameters during treatment (see section "Adverse reactions").

In case of severe hematological toxicity or development of transfusion dependence, treatment with Lynparza should be discontinued, followed by appropriate hematological investigations. If blood counts remain clinically abnormal 4 weeks after temporary discontinuation of the medicinal product, bone marrow examination and/or cytogenetic blood analysis are recommended.

Myelodysplastic syndrome / acute myeloid leukemia

The overall incidence of myelodysplastic syndrome / acute myeloid leukemia (MDS/AML) in patients receiving monotherapy with Lynparza in clinical trials, including long-term survival follow-up, was < 1.5%. Higher incidence was observed in patients with platinum-sensitive recurrent ovarian cancer and BRCA gene mutation who had received at least two prior lines of platinum-based chemotherapy and were followed for up to 5 years (see section "Adverse reactions"). Most events were fatal. Duration of olaparib therapy in patients who developed MDS/AML ranged from < 6 months to > 4 years.

If MDS/AML is suspected, patients should be referred to a hematologist for further investigations, including bone marrow examination and cytogenetic blood analysis. If MDS/AML is confirmed following evaluation of prolonged hematological toxicity, treatment with Lynparza should be discontinued and appropriate management initiated.

Venous thromboembolic complications

Venous thromboembolic complications, predominantly pulmonary embolism, have been reported in patients receiving Lynparza who did not have stable clinical conditions. A higher incidence of such events was observed in patients with metastatic castration-resistant prostate cancer who were also receiving androgen deprivation therapy, compared to use for other approved indications (see section "Adverse reactions").

Patients should be monitored for clinical signs and symptoms of venous thrombosis and pulmonary embolism and managed appropriately as clinically indicated. Patients with a history of venous thromboembolic complications may be at increased risk of future events and require careful monitoring.

Pneumonitis

Cases of pneumonitis, including fatal cases, have been reported in < 1.0% of patients receiving Lynparza in clinical trials. Pneumonitis cases lacked a clear clinical picture and could be confused with similar conditions caused by multiple factors (lung cancer and/or lung metastases, underlying lung disease, history of smoking, and/or prior chemotherapy or radiotherapy). In the event of new or worsening respiratory symptoms such as dyspnea, cough, or fever, or chest X-ray abnormalities, treatment with Lynparza should be discontinued and prompt investigations initiated. If pneumonitis is confirmed, treatment with Lynparza should be discontinued and appropriate management provided.

Hepatotoxicity

Cases of hepatotoxicity have been reported in patients receiving olaparib (see section "Adverse reactions"). If clinical symptoms or signs suggestive of hepatotoxicity occur, prompt clinical evaluation and liver function tests should be performed. Treatment should be interrupted if drug-induced liver injury (DILI) is suspected. Discontinuation of treatment should be considered clinically appropriate in cases of severe DILI.

Embryo-fetal toxicity

Due to its mechanism of action (inhibition of poly [ADP-ribose] polymerase [PARP]), Lynparza may cause harm to the fetus if used during pregnancy. In preclinical studies, olaparib caused adverse effects on embryo-fetal survival in rats and significant fetal malformations at exposures lower than those expected with recommended human dosing (300 mg twice daily).

Pregnancy / contraceptive methods

Lynparza must not be used during pregnancy. Women of reproductive potential must use two reliable forms of contraception before initiating treatment with Lynparza, during therapy, and for 6 months after the last dose. Two highly effective, complementary contraceptive methods are recommended. Male patients and their female partners of reproductive potential must use a reliable method of contraception during treatment and for 3 months after the last dose of Lynparza (see section "Use during pregnancy or breastfeeding").

Interactions

Concomitant use of strong or moderate CYP3A inhibitors with Lynparza is not recommended (see section "Interaction with other medicinal products and other forms of interaction"). If co-administration of a strong or moderate CYP3A inhibitor is necessary, the dose of Lynparza should be reduced (see sections "Posology and method of administration" and "Interaction with other medicinal products and other forms of interaction").

Concomitant use of Lynparza with strong or moderate CYP3A inducers is not recommended. If a patient receiving Lynparza requires treatment with a strong or moderate CYP3A inducer, the prescribing physician should be aware that the efficacy of Lynparza may be substantially reduced (see section "Interaction with other medicinal products and other forms of interaction").

Sodium

Lynparza contains less than 1 mmol sodium (23 mg) per tablet containing 100 mg or 150 mg of olaparib, and is therefore considered essentially "sodium-free".

Use during pregnancy or breastfeeding

Women of reproductive potential / contraception in women

Women of reproductive potential must not become pregnant while receiving Lynparza or at the start of treatment. All women of reproductive potential must undergo pregnancy testing before initiation of therapy and regularly throughout the treatment period.

Before starting treatment with Lynparza, women of reproductive potential must use two reliable forms of contraception and continue their use during therapy and for 6 months after the last dose of Lynparza, unless abstinence is the chosen method of contraception (see section "Special precautions for use"). Two highly effective, complementary contraceptive methods are recommended.

Since olaparib may potentially reduce exposure of CYP2C9 substrates by inducing this enzyme, the effectiveness of certain hormonal contraceptives used concomitantly with olaparib may be reduced. Therefore, the use of additional non-hormonal contraceptive methods should be considered during treatment (see section "Interaction with other medicinal products and other forms of interaction"). Women with hormone-dependent cancers should consider using two non-hormonal contraceptive methods.

Contraception in men

It is unknown whether olaparib or its metabolites are excreted in semen. During treatment and for 3 months after the last dose of Lynparza, male patients must use condoms during sexual intercourse with a pregnant woman or a woman of reproductive potential. Female partners of male patients of reproductive potential must also use a highly effective method of contraception (see section "Special precautions for use"). Male patients must not donate sperm during treatment and for 3 months after the last dose of Lynparza.

Pregnancy

In animal studies, toxic effects on reproductive function were observed, including serious teratogenic effects and effects on embryo-fetal survival in rats at systemic exposures lower than those in humans receiving therapeutic doses. There are no data on the use of olaparib in pregnant women. However, due to the mechanism of action of olaparib, Lynparza must not be used in pregnant women or in women of reproductive potential who are not using a reliable method of contraception during treatment and for 6 months after the last dose (for further information on contraception methods and pregnancy testing, see the previous section "Women of reproductive potential / contraception in women").

Breastfeeding

Studies on the excretion of olaparib into breast milk in animals have not been conducted. It is unknown whether olaparib or its metabolites are excreted in human breast milk. Due to the pharmacological properties of Lynparza, its use during breastfeeding and for 1 month after the last dose is contraindicated (see section "Contraindications").

Fertility

Clinical data on the effect on fertility are lacking. In animal studies, no effect on fertility was observed, but adverse effects on embryo-fetal survival were noted.

Ability to affect the rate of reactions when driving or operating machinery

Lynparza has a moderate influence on the ability to drive or operate machinery. Patients receiving Lynparza may experience fatigue, asthenia, or dizziness. Patients experiencing these symptoms should exercise caution when driving or operating machinery.

Method of Administration and Dosage

Treatment with the medicinal product Lynparza should be initiated and conducted under the supervision of a physician experienced in the use of anticancer medicinal products.

Patient Selection

First-line maintenance therapy for BRCA-mutated advanced ovarian cancer

Prior to prescribing the medicinal product Lynparza as a first-line maintenance therapy for high-grade epithelial ovarian cancer (EOC), fallopian tube cancer (FTC), or primary peritoneal cancer (PPC), patients must have confirmed or suspected deleterious germline and/or somatic mutations in the breast cancer susceptibility gene (BRCA) 1 or 2, as determined by a validated test.

Platinum-sensitive relapsed ovarian cancer maintenance therapy

Prior to using the medicinal product Lynparza for maintenance monotherapy in relapsed EOC, FTC, or PPC in patients who have achieved a complete or partial response to platinum-based therapy, testing for BRCA1/2 gene mutation is not required.

First-line maintenance therapy for HRD-positive advanced ovarian cancer in combination with bevacizumab

Prior to prescribing the medicinal product Lynparza with bevacizumab as first-line maintenance therapy for EOC, FTC, or PPC, patients must have confirmed or suspected deleterious BRCA1/2 gene mutations and/or confirmed genomic instability as determined by a validated test (see section "Pharmacodynamics").

Adjuvant therapy for early-stage high-risk breast cancer with germline BRCA mutations

Before prescribing the medicinal product Lynparza for adjuvant therapy of early-stage, high-risk, HER2-negative breast cancer, confirmation or suspicion of a deleterious germline BRCA1/2 gene mutation must be established using a validated test (see section "Pharmacodynamics").

Monotherapy for HER2-negative metastatic breast cancer with BRCA1/2 mutation (gBRCA1/2)

For locally advanced or metastatic HER2-negative breast cancer (where HER2 is human epidermal growth factor receptor 2) with a germline mutation in the breast cancer susceptibility gene (gBRCA1/2), prior to prescribing Lynparza, patients must have confirmed or suspected deleterious gBRCA1/2 mutation. The gBRCA1/2 mutation status must be determined by experienced laboratory personnel using a validated testing method. There are currently no data confirming the clinical validity of BRCA1/2 tumor testing in breast cancer.

First-line maintenance therapy for metastatic BRCA-mutated pancreatic adenocarcinoma

Prior to prescribing the medicinal product Lynparza as a first-line maintenance therapy for metastatic pancreatic adenocarcinoma with BRCA1/2 mutation, patients must have confirmed or suspected deleterious gBRCA1/2 mutation. The gBRCA1/2 mutation status must be determined by experienced laboratory personnel using a validated testing method. There are currently no data confirming the clinical validity of BRCA1/2 tumor testing in pancreatic adenocarcinoma.

Monotherapy for metastatic castration-resistant prostate cancer with BRCA1/2 mutations

Prior to prescribing the medicinal product Lynparza for the treatment of metastatic castration-resistant prostate cancer (mCRPC) with BRCA1/2 mutations, patients must have confirmed or suspected deleterious BRCA1/2 gene mutations (tested using tumor or blood samples) (see section "Pharmacodynamics"). The BRCA1/2 mutation status must be determined by experienced laboratory personnel using a validated test.

Treatment of mCRPC with Lynparza in combination with abiraterone and prednisone or prednisolone

Genetic testing is not required prior to prescribing Lynparza in combination with abiraterone and prednisone or prednisolone for the treatment of patients with mCRPC.

Genetic counseling should be provided to patients undergoing BRCA1/2 gene mutation testing in accordance with local guidelines.

Dosage

The medicinal product Lynparza is available in 100 mg and 150 mg tablet formulations.

The recommended dose of Lynparza, whether used as monotherapy or in combination with bevacizumab (for ovarian cancer treatment), abiraterone and prednisone or prednisolone (for prostate cancer treatment), or endocrine therapy, is 300 mg (two 150 mg tablets) twice daily, equivalent to a total daily dose of 600 mg. 100 mg tablets are available for dose reduction.

Monotherapy with Lynparza

Patients with platinum-sensitive relapsed high-grade epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who have achieved a response (complete or partial) to platinum-based chemotherapy should initiate treatment with Lynparza no later than 8 weeks after the last dose of platinum therapy.

Lynparza in combination with bevacizumab

When Lynparza is used in combination with bevacizumab as first-line maintenance therapy for high-grade epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer following completion of first-line platinum-based chemotherapy, the dose of bevacizumab is 15 mg/kg every 3 weeks. See complete information on bevacizumab (see section "Pharmacodynamics").

Lynparza in combination with endocrine therapy

Dosage information is provided in the detailed instructions for the endocrine therapy component(s) (aromatase inhibitor / antiestrogenic agent and/or LHRH analogue).

Lynparza in combination with abiraterone and prednisone or prednisolone

When Lynparza is used in combination with abiraterone for the treatment of patients with mCRPC, the dose of abiraterone is 1000 mg orally once daily (see section "Pharmacodynamics"). Abiraterone should be administered with prednisone or prednisolone at a dose of 5 mg orally twice daily. Complete information on abiraterone is provided in the medicinal product's instructions for medical use.

Duration of Treatment

First-line maintenance therapy for BRCA-mutated advanced ovarian cancer

Patients may continue treatment until radiologically confirmed disease progression, until unacceptable toxicity occurs, or for up to 2 years if no disease progression is radiologically confirmed after 2 years of treatment. Patients in whom disease is confirmed after 2 years of treatment and who, in the opinion of the treating physician, may benefit from continued therapy, may continue treatment beyond 2 years.

Platinum-sensitive relapsed ovarian cancer maintenance therapy

Patients with platinum-sensitive relapsed high-grade epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer should continue treatment until disease progression or until unacceptable toxicity occurs.

First-line maintenance therapy for HRD-positive advanced ovarian cancer in combination with bevacizumab

Patients may continue treatment with Lynparza until radiologically confirmed disease progression, until unacceptable toxicity occurs, or for up to 2 years if no disease progression is radiologically confirmed after 2 years of treatment. Patients in whom disease is confirmed after 2 years of treatment and who, in the opinion of the treating physician, may benefit from continued treatment with Lynparza, may continue treatment beyond 2 years. See information on bevacizumab regarding the recommended total duration of treatment, which is up to 15 months, including periods combined with chemotherapy and as maintenance therapy (see section "Pharmacodynamics").

Adjuvant therapy for early-stage high-risk breast cancer with germline BRCA mutations

Treatment is recommended for up to 1 year or until disease recurrence or development of unacceptable toxicity, whichever occurs first.

Monotherapy for HER2-negative metastatic breast cancer with germline BRCA1/2 mutation (gBRCA1/2)

Treatment should be continued until disease progression or the occurrence of unacceptable toxic effects.

There are no data on the efficacy or safety of maintenance therapy with Lynparza after first or subsequent relapse in patients with ovarian cancer. There are no data on the efficacy or safety of re-treatment in patients with breast cancer (see section "Pharmacodynamics").

First-line maintenance therapy for metastatic pancreatic adenocarcinoma with germline BRCA mutation

Treatment should be continued until disease progression or the occurrence of unacceptable toxicity.

Monotherapy for metastatic castration-resistant prostate cancer with BRCA1/2 mutations

Treatment should be continued until disease progression or the occurrence of unacceptable toxic effects. During treatment, patients who have not undergone surgical castration must continue medical castration using a luteinizing hormone-releasing hormone (LHRH) analogue.

Treatment of mCRPC with Lynparza in combination with abiraterone and prednisone or prednisolone

When Lynparza is used in combination with abiraterone and prednisone or prednisolone, treatment should be continued until disease progression or the occurrence of unacceptable toxic effects. Treatment with a gonadotropin-releasing hormone (GnRH) analogue should be continued during treatment in all patients, or patients must have undergone prior bilateral orchidectomy. Information on abiraterone is provided in the medicinal product's instructions for medical use.

There are no data on the efficacy or safety of re-treatment with Lynparza in patients with prostate cancer (see section "Pharmacodynamics").

Missed Dose

If a patient misses a dose of Lynparza, the next dose should be taken at the usual time.

Dose Adjustment for Adverse Reactions

Treatment may be interrupted to manage adverse reactions such as nausea, vomiting, diarrhea, and anemia. Dose reduction may be necessary (see section "Adverse Reactions").

The recommended dose reduction is to 250 mg (one 150 mg tablet and one 100 mg tablet) twice daily (equivalent to a total daily dose of 500 mg).

If further dose reduction is required, the dose should be reduced to 200 mg (two 100 mg tablets) twice daily (equivalent to a total daily dose of 400 mg).

Dose Adjustment of the Medicinal Product with Concomitant CYP3A Inhibitors

Concomitant use of strong or moderate CYP3A inhibitors is not recommended. Alternative agents should be considered. If concomitant use of a strong CYP3A inhibitor is necessary, the dose of Lynparza should be reduced to 100 mg (one 100 mg tablet) twice daily (equivalent to a total daily dose of 200 mg). If concomitant use of a moderate CYP3A inhibitor is necessary, the dose of Lynparza should be reduced to 150 mg (one 150 mg tablet) twice daily (equivalent to a total daily dose of 300 mg) (see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction").

Special Patient Populations

Elderly Patients

Elderly patients do not require adjustment of the initial dose.

Renal Impairment

For patients with moderate renal impairment (creatinine clearance 31–50 mL/min), the recommended dose of Lynparza is 200 mg (two 100 mg tablets) twice daily (equivalent to a total daily dose of 400 mg) (see section "Pharmacokinetics").

Patients with mild renal impairment (creatinine clearance 51–80 mL/min) may take Lynparza without dose adjustment.

Lynparza is not recommended for patients with severe renal impairment or end-stage renal disease (creatinine clearance ≤ 30 mL/min), as safety and pharmacokinetics have not been studied in these patients. Lynparza may be prescribed to patients with severe renal impairment only if the benefit outweighs the risk. In such cases, patients require careful monitoring of renal function and adverse reactions.

Hepatic Impairment

Lynparza may be administered to patients with mild to moderate hepatic impairment (Child-Pugh class A or B) without dose adjustment (see section "Pharmacokinetics"). Lynparza is not recommended for patients with severe hepatic impairment (Child-Pugh class C), as safety and pharmacokinetics have not been studied in these patients.

Patients of Non-European Ancestry

Clinical data in patients of non-European ancestry are limited. However, dose adjustment based on ethnicity is not required (see section "Pharmacokinetics").

Method of Administration

Lynparza is intended for oral administration.

Film-coated tablets should be swallowed whole, without chewing, crushing, dissolving, or dividing. Film-coated tablets may be taken with or without food.

Children

Safety and efficacy of Lynparza in children and adolescents have not been studied. Data are lacking.

Overdose

Experience with olaparib overdose is limited. In a small number of patients who received olaparib in tablet form at a daily dose of up to 900 mg for two days, no unexpected adverse reactions were observed. Symptoms of overdose are not defined, and there is no specific antidote for Lynparza overdose. In case of overdose, physicians should implement general supportive measures and provide symptomatic treatment.

Adverse Reactions

Summary of Safety Profile

Adverse reactions observed during treatment with the medicinal product Lynparza were mostly of mild or moderate severity (Grade 1 or 2 according to the Common Terminology Criteria for Adverse Events [CTCAE]), and generally did not require discontinuation of the medicinal product. The most commonly reported adverse reactions in clinical trials among patients receiving Lynparza monotherapy (≥10%) were nausea, fatigue/asthenia, anemia, vomiting, diarrhea, decreased appetite, headache, neutropenia, dysgeusia, cough, leukopenia, dizziness, dyspnea, and dyspepsia.

Adverse reactions of Grade ≥3 occurring in >2% of patients were anemia (14%), neutropenia (5%), fatigue/asthenia (4%), leukopenia (2%), and thrombocytopenia (2%).

The most common adverse reactions leading to treatment interruption and/or dose reduction during monotherapy were anemia (16%), nausea (7%), fatigue/asthenia (6%), neutropenia (6%), and vomiting (6%). The most frequent adverse reactions leading to complete discontinuation of the medicinal product were anemia (1.7%), nausea (0.9%), fatigue/asthenia (0.8%), thrombocytopenia (0.7%), neutropenia (0.6%), and vomiting (0.5%).

When Lynparza is used in combination with bevacizumab for the treatment of ovarian cancer or in combination with abiraterone and prednisone or prednisolone for the treatment of prostate cancer, the safety profile is generally consistent with the safety profiles of each of these medicinal products when used as monotherapy.

Adverse reactions led to interruption of olaparib treatment and/or dose reduction in 57% of patients when used in combination with bevacizumab, and to complete discontinuation of treatment with olaparib/bevacizumab and placebo/bevacizumab in 21% and 6% of patients, respectively. The most common adverse reactions leading to treatment interruption and/or dose reduction were anemia (21.7%), nausea (9.5%), fatigue/asthenia (5.4%), vomiting (3.7%), neutropenia (3.6%), thrombocytopenia (3.0%), and diarrhea (2.6%). The most common adverse reactions leading to complete discontinuation of the medicinal product were anemia (3.7%), nausea (3.6%), and fatigue/asthenia (1.5%).

Adverse reactions led to interruption of olaparib treatment and/or dose reduction in 50.7% of patients when used in combination with abiraterone, and to complete discontinuation of treatment with olaparib/abiraterone and placebo/abiraterone in 19.0% and 8.8% of patients, respectively. The most common adverse reactions leading to interruption of treatment and/or dose reduction were anemia (17.1%), fatigue/asthenia (5.5%), nausea (4.1%), neutropenia (3.4%), vomiting (2.3%), diarrhea (2.1%), and venous thrombotic events (2.1%). The most common adverse reactions leading to complete discontinuation of the medicinal product were anemia (4.5%) and fatigue/asthenia (1.3%).

List of Adverse Reactions in Tabular Form

The safety profile is based on pooled data from 4,499 patients with solid tumors who received Lynparza monotherapy at the recommended dose in clinical trials.

The adverse reactions listed below were identified in clinical trials of patients receiving Lynparza monotherapy with known exposure. Adverse drug reactions are presented in Table 14 according to the Medical Dictionary for Regulatory Activities (MedDRA) classification by System Organ Class (SOC) and Preferred Term. Within each SOC, adverse reactions are listed by Preferred Term in order of decreasing frequency and clinical significance. Adverse reactions are categorized by frequency as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from available data).

Table 16

a MDS/AML includes the following preferred terms (PTs): acute myeloid leukaemia, myelodysplastic syndrome, and myeloid leukaemia.

Anaemia includes the following PTs: anaemia, macrocytic anaemia, erythropenia, decreased haematocrit, decreased haemoglobin, normocytic anaemia, and decreased red blood cell count.

Neutropenia includes the following PTs: febrile neutropenia, neutropenia, neutropenic infection, neutropenic sepsis, and decreased neutrophil count.

Thrombocytopenia includes the following PTs: decreased platelet count and thrombocytopenia.

Leukopenia includes the following PTs: leukopenia and decreased white blood cell count.

Lymphopenia includes the following PTs: decreased lymphocyte count and lymphopenia.

Hypersensitivity includes the following PTs: drug hypersensitivity and hypersensitivity.

Increased transaminases includes the following PTs: increased alanine aminotransferase, increased aspartate aminotransferase, increased liver enzymes, and hypertransaminasaemia.

Dysgeusia includes the following PTs: dysgeusia and taste disorders.

Cough includes the following PTs: cough and productive cough.

Dyspnoea includes the following PTs: dyspnoea and exertional dyspnoea.

Stomatitis includes the following PTs: aphthous stomatitis, oral ulceration, and stomatitis.

Rash includes the following PTs: erythema, exfoliative rash, rash, erythematous rash, macular rash, maculopapular rash, papular rash, and rash with pruritus.

Dermatitis includes the following PTs: dermatitis and allergic dermatitis.

Venous thromboembolic complications include the following PTs: embolism, pulmonary embolism, thrombosis, deep vein thrombosis, vena cava thrombosis, and venous thrombosis.

b Laboratory data are presented below under the subheadings “Haematological toxicity” and “Other laboratory results”.

* Based on post-marketing experience.

Description of selected adverse reactions

Haematological toxicity

Anaemia and other manifestations of haematological toxicity were generally of low grade (Grade 1 or 2 according to CTCAE); however, Grade 3 and higher reactions according to CTCAE were observed. The most common adverse reaction ≥ Grade 3 according to CTCAE in clinical trials was anaemia. The median time to first occurrence of anaemia was approximately 4 weeks (approximately 7 weeks for events ≥ Grade 3 according to CTCAE). Anaemia was managed by treatment interruption and dose reduction (see section “Dosage and administration”), and, if necessary, by red blood cell transfusion. In clinical trials of the tablet formulation of the medicinal product, the frequency of adverse reactions of anaemia was 35.2% (≥ Grade 3 according to CTCAE – 14.8%), and the frequencies of treatment discontinuation, dose reduction, and drug withdrawal due to anaemia were 16.4%, 11.1%, and 2.1%, respectively. 15.6% of patients receiving olaparib required one or more red blood cell transfusions. A dose-dependent decrease in haemoglobin levels with olaparib has been demonstrated. In clinical trials of the medicinal product Lynparza, the frequency of changes (decreases) from baseline levels ≥ Grade 2 according to CTCAE was as follows: haemoglobin – 21%, absolute neutrophil count – 17%, platelets – 5%, lymphocytes – 26%, and leukocytes – 19% (all values are approximate).

The frequency of increases in mean corpuscular volume (MCV) from low or normal to above the upper limit of normal (ULN) was approximately 51%. After treatment discontinuation, values returned to normal without clinical consequences.

It is recommended to perform a complete blood count at baseline and repeat monthly for the first 12 months of treatment, and periodically thereafter, to monitor for clinically significant changes in any parameters during treatment that may require treatment interruption or dose reduction and/or further management (see sections “Dosage and administration” and “Special warnings and precautions for use”).

Myelodysplastic syndrome / acute myeloid leukaemia

MDS/AML are serious adverse reactions that occurred infrequently in clinical trials of olaparib monotherapy administered at therapeutic doses across all indications (0.9%). The incidence was 0.5%, including events recorded during long-term safety follow-up (incidence calculated based on the overall population of 18,576 patients who received at least one dose of oral olaparib in clinical trials). All patients had potential risk factors for developing MDS/AML, as they had previously received platinum-based chemotherapy. Many of them had also received other DNA-damaging agents and radiotherapy. In most cases, these events occurred in carriers of germline mutations in the breast cancer susceptibility gene 1 or 2 (gBRCA1/2). The incidence of MDS/AML was similar in patients with gBRCA1m and gBRCA2m (1.6% and 1.2%, respectively). Some patients had a history of malignancies or bone marrow dysplasia.

In patients with platinum-sensitive relapsed ovarian cancer and BRCA mutation who had received at least two prior lines of platinum-based chemotherapy and the investigational medicinal product prior to disease progression (study SOLO2, with olaparib tablet formulation administered for ≥ 2 years in 45% of patients), the prevalence of MDS/AML was 8% in the olaparib group and 4% in the placebo group after 5 years of follow-up. In the olaparib group, 9 out of 16 cases of MDS/AML occurred after olaparib discontinuation during the survival follow-up period. The incidence of MDS/AML was considered in the context of prolonged overall survival in the olaparib group and the late onset of MDS/AML. The risk of MDS/AML remains low in patients receiving first-line therapy, where maintenance olaparib was administered after one line of platinum-based chemotherapy for 2 years (in study SOLO1, this risk was 1.5% over 7 years of follow-up, and in study PAOLA-1, 1.1% over 5 years of follow-up). For information on risk reduction and management, see section “Special warnings and precautions for use”.

Venous thromboembolic complications

In men receiving olaparib in combination with abiraterone as first-line treatment for mCRPC (study PROpel), the incidence of venous thromboembolic complications was 8% in the olaparib plus abiraterone group and 3.3% in the placebo plus abiraterone group. The median time to event in this study was 170 days (range 12 to 906 days). Most patients recovered from the complication and were able to continue olaparib treatment in combination with standard medical therapy.

Patients with serious cardiovascular diseases were excluded from the studies. Exclusion criteria for patients with cardiovascular diseases are described in the abiraterone medicinal product information (see section “Special warnings and precautions for use”).

Other laboratory parameters

In clinical trials of the medicinal product Lynparza, the frequency of changes (increases) in blood creatinine levels from baseline ≥ Grade 2 according to CTCAE was approximately 11%. Data from a double-blind, placebo-controlled trial showed that the median increase in this parameter by 23% from baseline remained relatively stable over time. The parameter returned to baseline values after treatment discontinuation. No clinical consequences of this change were observed. At study entry, 90% of patients had creatinine level changes of Grade 0 according to CTCAE and 10% had changes of Grade 1 according to CTCAE.

Gastrointestinal toxicities

Nausea was generally observed very early. In most patients, it first occurred within the first month of treatment with Lynparza. Vomiting was observed early, with most patients experiencing it for the first time within the first two months of Lynparza treatment. Most patients experienced either nausea or vomiting. These were managed by treatment interruption, dose reduction, and/or antiemetic therapy. Prophylactic antiemetic treatment is not required.

In first-line maintenance treatment of ovarian cancer in female patients, nausea (77% of patients receiving olaparib, 38% receiving placebo), vomiting (40% of patients receiving olaparib, 15% receiving placebo), diarrhoea (34% of patients receiving olaparib, 25% receiving placebo), and dyspepsia (17% of patients receiving olaparib, 12% receiving placebo) were reported. Nausea led to drug discontinuation in 2.3% of patients receiving olaparib (Grade 2 according to CTCAE) and in 0.8% of patients receiving placebo (Grade 1 according to CTCAE). Vomiting and dyspepsia of low grade (Grade 2 according to CTCAE) led to treatment discontinuation in 0.8% and 0.4% of patients receiving olaparib, respectively. No patient receiving olaparib or placebo discontinued treatment due to diarrhoea. No patient receiving placebo discontinued treatment due to vomiting or dyspepsia. Nausea led to treatment interruption and dose reduction in 14% and 4% of patients receiving olaparib, respectively. Vomiting led to treatment interruption in 10% of patients receiving olaparib. No vomiting led to dose reduction in any patient receiving olaparib.

Pediatric population

Clinical studies in paediatric patients have not been conducted.

Other special patient groups

Safety data in patients of non-Caucasian race are limited.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life

48 months.

Storage conditions

Store in the original packaging to protect from moisture. The medicinal product does not require special storage conditions. Keep out of the reach of children.

Packaging

8 film-coated tablets in a blister; 7 blisters in a cardboard box.

Prescription status

Prescription only.

Manufacturer

1. AstraZeneca UK Limited.
2. AstraZeneca AB.

Manufacturer's address and place of business

1. Silk Road Business Park, Macclesfield, SK10 2NA, United Kingdom.
2. Gertunavägen, Södertälje, 152 57, Sweden.