LYNPARZA Film-coated tablet Ref.[8404] Active ingredients: Olaparib

Pharmacotherapeutic group: antineoplastic agents, other antineoplastic agents
ATC code: L01XX46

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), and has been shown to inhibit the growth of selected tumour cell lines in vitro and tumour growth in vivo either as a standalone treatment or in combination with established chemotherapies.

PARPs are required for the efficient repair of DNA single strand breaks and an important aspect of PARP-induced repair requires that after chromatin modification, PARP auto-modifies itself and dissociates from the DNA to facilitate access for base excision repair (BER) enzymes. When olaparib is bound to the active site of DNA-associated PARP it prevents the dissociation of PARP and traps it on the DNA, thus blocking repair. In replicating cells this also leads to the formation of DNA double-strand breaks (DSBs) when replication forks meet the PARP-DNA adducts. In normal cells, homologous recombination repair (HRR) pathway is effective at repairing these DNA DSBs. In cancers that lack functional components of HRR such as BRCA1 or 2, DNA DSBs cannot be repaired accurately or effectively. Instead, alternative and error-prone pathways are activated, such as the classical non-homologous end joining (NHEJ) pathway, leading to increased genomic instability. After a number of rounds of replication, genomic instability can reach insupportable levels and result in cancer cell death, as cancer cells already have a high DNA damage load relative to normal cells. In the absence of BRCA1 or BRCA2 mutations, HRR pathway may be compromised by other mechanisms, although the causative aberrancy and penetrance are not fully elucidated. Absence of fully functional HRR pathway is one of the key determinants of platinum sensitivity in ovarian and other cancers.

In BRCA1/2-deficient in vivo models, olaparib given after platinum treatment resulted in a delay in tumour progression and an increase in overall survival compared to platinum treatment alone that correlated with the period of olaparib maintenance treatment.

Detection of BRCA1/2 mutations

Local or central testing of blood and/or tumour samples for BRCA1/2 mutations have been used in different studies. Depending on the test used and the international classification consensus, the BRCA1/2 mutations have been classified as deleterious/suspected deleterious or pathogenic/likely pathogenic. Genetic testing should be conducted by an experienced laboratory using a validated test.

Clinical efficacy and safety

First-line maintenance treatment of BRCA-mutated advanced ovarian cancer

SOLO1 Study

The safety and efficacy of olaparib as maintenance therapy were studied in patients with newly diagnosed advanced (FIGO Stage III-IV) high-grade serous or endometrioid BRCA1/2 mutated (BRCA1/2m) ovarian cancer following completion of first-line platinum-based chemotherapy in a Phase III randomised, double-blind, placebo-controlled, multicentre trial. In this study 391 patients were randomised 2:1 to receive either Lynparza (300 mg [2 × 150 mg tablets] twice daily) or placebo. Patients were stratified by response to first-line platinum chemotherapy; complete response (CR) or partial response (PR). Treatment was continued until radiological progression of the underlying disease, unacceptable toxicity or for up to 2 years. For patients who remained in complete clinical response (i.e. no radiological evidence of disease), the maximum duration of treatment was 2 years; however, patients who had evidence of disease that remained stable (i.e. no evidence of disease progression) could continue to receive Lynparza beyond 2 years.

Patients with germline or somatic BRCA1/2 mutations were identified prospectively either from germline testing in blood via a local test (n=208) or central test (n=181) or from testing a tumour sample using a local test (n=2). By central germline testing, deleterious or suspected deleterious mutations were identified in 95.3% (365/383) and 4.7% (18/383) of patients, respectively. Large rearrangements in the BRCA1/2 genes were detected in 5.5% (21/383) of the randomised patients. The gBRCAm status of patients enrolled via local testing was confirmed retrospectively by central testing. Retrospective testing of patients with available tumour samples was performed using central testing and generated successful results in 341 patients, of which 95% had an eligible mutation (known [n=47] or likely pathogenic [n=277]) and 2 gBRCAwt patients were confirmed to have sBRCAm only. There were 389 patients who were germline BRCA1/2m and 2 who were somatic BRCA1/2m in SOLO1.

Demographic and baseline characteristics were generally well balanced between the olaparib and placebo treatment arms. Median age was 53 years in both arms. Ovarian cancer was the primary tumour in 85% of the patients. The most common histological type was serous (96%), endometrioid histology was reported in 2% of the patients. Most patients were ECOG performance status 0 (78%), there are no data in patients with performance status 2 to 4. Sixty-three percent (63%) of the patients had upfront debulking surgery and of these the majority (75%) had no macroscopic residual disease. Interval debulking surgery was performed in 35% of the patients and of these 82% had no macroscopic residual disease reported. Seven patients, all stage IV, had no cytoreductive surgery. All patients had received first-line platinum-based therapy. There was no evidence of disease at study entry (CR), defined by the investigator as no radiological evidence of disease and cancer antigen 125 (CA-125) within normal range, in 73% and 77% of patients in the olaparib and placebo arms, respectively. PR, defined as the presence of any measurable or non-measurable lesions at baseline or elevated CA-125, was reported in 27% and 23% of patients in the olaparib and placebo arms, respectively. Ninety three percent (93%) of patients were randomised within 8 weeks of their last dose of platinum-based chemotherapy. Patients who had been treated with bevacizumab were excluded from the study, therefore there are no safety and efficacy data on olaparib patients who had previously received bevacizumab. There are very limited data in patients with a somatic BRCA mutation.

The primary endpoint was progression-free survival (PFS) defined as time from randomisation to progression determined by investigator assessment using modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, or death. Secondary efficacy endpoints included time from randomisation to second progression or death (PFS2), overall survival (OS), time from randomisation to discontinuation of treatment or death (TDT), time from randomisation to first subsequent anti-cancer therapy or death (TFST) and health related quality of life (HRQoL). Patients had tumour assessments at baseline and every 12 weeks for 3 years, and then every 24 weeks relative to date of randomisation, until objective radiological disease progression.

The study demonstrated a clinically relevant and statistically significant improvement in investigator assessed PFS for olaparib compared to placebo. The investigator assessment of PFS was supported with a blinded independent central radiological (BICR) review of PFS. At the time of PFS analysis, interim OS data were immature (21%), with HR 0.95 (95% CI 0.60, 1.53; p-value=0.9). Efficacy results are presented in Table 2 and Figures 1 and 2.

Table 2. Efficacy results for newly diagnosed patients with BRCA1/2m advanced ovarian cancer in SOLO1:

^a Based on Kaplan-Meier estimates, the proportion of patients that were progression free at 24 and 36 months were 74% and 60% for olaparib versus 35% and 27% for placebo; the median follow-up time was 41 months for both the olaparib and placebo arms.
^b A value <1 favours olaparib. The analysis was performed using a Cox proportional hazards model including response to previous platinum chemotherapy (CR or PR) as a covariate.
^c Of the 94 patients on the placebo arm who received subsequent therapy, 49 (52%) received a PARP inhibitor.
* Not controlled for multiplicity.
^bd Twice daily; NR Not reached; CI Confidence interval; PFS Progression-free survival; PFS2 Time to second progression or death; OS Overall survival; TFST Time from randomisation to first subsequent anti-cancer therapy or death.

Figure 1. SOLO1: Kaplan-Meier plot of PFS in newly diagnosed patients with BRCA1/2m advanced ovarian cancer (51% maturity – investigator assessment):

Figure 2. SOLO1: Kaplan-Meier plot of OS in newly diagnosed patients with BRCA1/2m advanced ovarian cancer (21% maturity):

Consistent results were observed in the subgroups of patients by evidence of the disease at study entry. Patients with CR defined by the investigator had HR 0.34 (95% CI 0.24–0.47); median PFS not reached on olaparib vs 15.3 months on placebo. At 24 and 36 months, respectively, 68% and 45% patients remained in CR in the olaparib arm, and 34% and 22% of patients in the placebo arm. Patients with PR at study entry had PFS HR 0.31 (95% CI 0.18, 0.52; median PFS 30.9 months on olaparib vs 8.4 months on placebo). Patients with PR at study entry either achieved CR (15% in olaparib arm and 4% in the placebo arm at 24 months, remained in CR at 36 months) or had further PR/stable disease (43% in olaparib arm and 15% in the placebo arm at 24 months; 17% in olaparib arm and 15% in placebo arm at 36 months). The proportion of patients who progressed within 6 months of the last dose of platinum-based chemotherapy was 3.5% for olaparib and 8.4% for placebo.

Maintenance treatment of platinum-sensitive relapsed (PSR) ovarian cancer

SOLO2 Study The safety and efficacy of olaparib as maintenance therapy were studied in a Phase III randomised, double-blind, placebo-controlled trial in patients with germline BRCA1/2-mutated PSR ovarian, fallopian tube or primary peritoneal cancer. The study compared the efficacy of Lynparza maintenance treatment (300 mg [2 × 150 mg tablets] twice daily) taken until progression with placebo treatment in 295 patients with high-grade serous or endometrioid PSR ovarian cancer (2:1 randomisation: 196 olaparib and 99 placebo) who were in response (CR or PR) following completion of platinum-containing chemotherapy.

Patients who have received two or more platinum-containing regimens and whose disease had recurred >6 months after completion of penultimate platinum-based chemotherapy were enrolled. Patients could not have received prior olaparib or other PARP inhibitor treatment. Patients could have received prior bevacizumab, except in the regimen immediately prior to randomisation.

All patients had evidence of gBRCA1/2m at baseline. Patients with BRCA1/2 mutations were identified either from germline testing in blood via a local test or by central testing at Myriad or from testing a tumour sample using a local test. Large rearrangements in the BRCA1/2 genes were detected in 4.7% (14/295) of the randomised patients.

Demographic and baseline characteristics were generally well balanced between the olaparib and placebo arms. Median age was 56 years in both arms. Ovarian cancer was the primary tumour in >80% of the patients. The most common histological type was serous (> 90%), endometrioid histology was reported in 6% of the patients. In the olaparib arm 55% of the patients had only 2 prior lines of treatment with 45% receiving 3 or more prior lines of treatment. In the placebo arm 61% of patients had received only 2 prior lines with 39% receiving 3 or more prior lines of treatment. Most patients were ECOG performance status 0 (81%), there are no data in patients with performance status 2 to 4. Platinum free interval was >12 months in 60% and >6-12 months in 40% of the patients. Response to prior platinum chemotherapy was complete in 47% and partial in 53% of the patients. In the olaparib and placebo arms, 17% and 20% of patients had prior bevacizumab, respectively.

The primary endpoint was PFS determined by investigator assessment using RECIST 1.1. Secondary efficacy endpoints included PFS2; OS, TDT, TFST, TSST; and HRQoL. The study met its primary objective demonstrating a statistically significant improvement in investigator assessed PFS for olaparib compared with placebo with a HR of 0.30 (95% CI 0.22-0.41; p<0.0001; median 19.1 months olaparib vs 5.5 months placebo). The investigator assessment of PFS was supported with a blinded independent central radiological review of PFS (HR 0.25; 95% CI 0.18-0.35; p<0.0001; median 30.2 months for olaparib and 5.5 months placebo). At 2 years, 43% olaparib-treated patients remained progression free compared with only 15% placebo-treated patients.

A summary of the primary objective outcome for patients with gBRCA1/2m PSR ovarian cancer in SOLO2 is presented in Table 3 and Figure 3.

Table 3. Summary of primary objective outcome for patients with gBRCA1/2m PSR ovarian cancer in SOLO2:

^a HR= Hazard Ratio. A value <1 favours olaparib. The analysis was performed using a Cox proportional hazard model including response to previous platinum chemotherapy (CR or PR), and time to disease progression (>6-12 months and >12 months) in the penultimate platinum-based chemotherapy as covariates.
^bd Twice daily; PFS progression-free survival; CI confidence interval

Figure 3. SOLO2: Kaplan-Meier plot of PFS in patients with gBRCA1/2m PSR ovarian cancer (63% maturity – investigator assessment):

The secondary endpoints TFST and PFS2 demonstrated a persistent and statistically significant improvement for olaparib compared with placebo (Table 4).

Table 4. Summary of key secondary objective outcomes for patients with gBRCA1/2m PSR ovarian cancer in SOLO2:

* Not controlled for multiplicity.
^a HR= Hazard Ratio. A value <1 favours olaparib. The analysis was performed using a Cox proportional hazard model including response to previous platinum chemotherapy (CR or PR), and time to disease progression (>6-12 months and >12 months) in the penultimate platinum-based chemotherapy as covariates.
^bd Twice daily; NR not reached; CI confidence interval; PFS2 time from randomisation to second progression or death; TFST Time from randomisation to start of first subsequent therapy or death.

Among the patients entering the trial with measurable disease (target lesions at baseline), an objective response rate of 41% was achieved in the Lynparza arm versus 17% on placebo. Of patients treated with Lynparza, who entered the study with evidence of disease (target or non-target lesions at baseline), 15.0% experienced complete response compared with 9.1% of patients on placebo.

At the time of the analysis of PFS the median duration of treatment was 19.4 months for olaparib and 5.6 months for placebo. The majority of patients remained on the 300 mg bd starting dose of olaparib. The incidence of dose interruptions, reductions, discontinuations due to an adverse event was 45.1%, 25.1% and 10.8%, respectively. Dose interruptions occurred most frequently in the first 3 months and dose reductions in the first 3-6 months of treatment. The most frequent adverse reactions leading to dose interruption or dose reduction were anaemia, nausea and vomiting.

Patient-reported outcome (PRO) data indicate no difference for the olaparib-treated patients as compared to placebo as assessed by the change from baseline in the TOI of the FACT-O.

Study 19 (D0810C00019)

The safety and efficacy of olaparib as a maintenance therapy in the treatment of PSR ovarian, including fallopian tube or primary peritoneal cancer patients, following treatment with two or more platinum-containing regimens, were studied in a large Phase II randomised, double-blind, placebo-controlled trial (Study 19). The study compared the efficacy of Lynparza capsule maintenance treatment (400 mg [8 × 50 mg capsules] twice daily) taken until progression with placebo treatment in 265 (136 olaparib and 129 placebo) PSR high grade serous ovarian cancer patients who were in response (CR or PR) following completion of platinum-containing chemotherapy. The primary endpoint was PFS based on investigator assessment using RECIST 1.0. Secondary efficacy endpoints included OS, disease control rate (DCR) defined as confirmed CR/PR + SD (stable disease), HRQoL and disease related symptoms. Exploratory analyses of TFST and TSST were also performed.

Patients whose disease had recurred >6 months after completion of penultimate platinum-based chemotherapy were enrolled. Enrolment did not require evidence of BRCA1/2 mutation (BRCA mutation status for some patients was determined retrospectively). Patients could not have received prior olaparib or other PARP inhibitor treatment. Patients could have received prior bevacizumab, except in the regimen immediately prior to randomisation. Retreatment with olaparib was not permitted following progression on olaparib.

Patients with BRCA1/2 mutations were identified either from germline testing in blood via a local test or by central testing at Myriad or from testing a tumour sample using a test performed by Foundation Medicine. Large rearrangements in the BRCA1/2 genes were detected in 7.4% (10/136) of the randomised patients.

Demographic and baseline characteristics were generally well balanced between the olaparib and placebo arms. Median age was 59 years in both arms. Ovarian cancer was the primary tumour in 86% of the patients. In the olaparib arm 44% of the patients had only 2 prior lines of treatment with 56% receiving 3 or more prior lines of treatment. In the placebo arm 49% of patients had received only 2 prior lines with 51% receiving 3 or more prior lines of treatment. Most patients were ECOG performance status 0 (77%), there are no data in patients with performance status 2 to 4. Platinum free interval was > 12 months in 60% and 6-12 months in 40% of the patients. Response to prior platinum chemotherapy was complete in 45% and partial in 55% of the patients. In the olaparib and placebo arms, 6% and 5% of patients had prior bevacizumab, respectively.

The study met its primary objective demonstrating a statistically significant improvement in PFS for olaparib compared with placebo in the overall population with a HR of 0.35 (95% CI 0.25-0.49; p<0.00001; median 8.4 months olaparib vs 4.8 months placebo). At the final OS analysis (data cut off [DCO] 9 May 2016) at 79% maturity, the hazard ratio comparing olaparib with placebo was 0.73 (95% CI 0.55-0.95; p=0.02138 [did not meet pre-specified significance level of <0.0095]; median 29.8 months olaparib versus 27.8 months placebo). In the olaparib-treated group, 23.5% (n=32/136) of patients remained on treatment for ≥2 years as compared with 3.9% (n=5/128) of the patients on placebo. Although patient numbers were limited, 13.2% (n=18/136) of the patients in the olaparib-treated group remained on treatment for ≥5 years as compared with 0.8% (n=1/128) in the placebo group.

Preplanned subgroup analysis identified patients with BRCA1/2-mutated ovarian cancer (n=136, 51.3%; including 20 patients identified with a somatic tumour BRCA ½ mutation) as the subgroup that derived the greatest clinical benefit from olaparib maintenance monotherapy. A benefit was also observed in patients with BRCA1/2 wild-type/variants of uncertain significance (BRCA1/2 wt/VUS), although of a lesser magnitude. There was no strategy for multiple testing in place for the sub-group analyses.

A summary of the primary objective outcome for patients with BRCA1/2-mutated and BRCA1/2 wt/VUS PSR ovarian cancer in Study 19 is presented in Table 4 and for all patients in Study 19 in Table 5 and Figure 4.

Table 5. Summary of primary objective outcome for all patients and patients with BRCA1/2-mutated and BRCA1/2 wt/VUS PSR ovarian cancer in Study 19:

^a All patients comprises of the following subgroups: BRCA1/2-mutated, BRCA1/2 wt/VUS and BRCA1/2 status unknown (11 patients with status unknown, not shown as a separate subgroup in table).
^b HR= Hazard Ratio. A value <1 favours olaparib. The analysis was performed using a Cox proportional hazards model with factors for treatment, ethnic descent, platinum sensitivity and response to final platinum therapy.
^bd Twice daily; PFS progression-free survival; DCO data cut off; CI confidence interval; NR not reached.

Figure 4. Study 19: Kaplan-Meier plot of PFS in the FAS (58% maturity – investigator assessment) DCO 30 June 2010:

A summary of key secondary objective outcomes for patients with BRCA1/2-mutated and BRCA1/2 wt/VUS PSR ovarian cancer in Study 19 is presented in Table 6 and for all patients in Study 19 in Table 6 and Figure 5.

Table 6. Summary of key secondary objective outcomes for all patients and patients with BRCA1/2-mutated and BRCA1/2 wt/VUS PSR ovarian cancer in Study 19:

Figure 5. Study 19: Kaplan Meier plot of OS in the FAS (79% maturity) DCO 09 May 2016:

At the time of the analysis of PFS the median duration of treatment was 8 months for olaparib and 4 months for placebo. The majority of patients remained on the 400 mg bd starting dose of olaparib. The incidence of dose interruptions, reductions and discontinuations due to an adverse event was 34.6%, 25.7% and 5.9%, respectively. Dose interruptions and reductions occurred most frequently in the first 3 months of treatment. The most frequent adverse reactions leading to dose interruption or dose reduction were nausea, anaemia, vomiting, neutropenia and fatigue. The incidence of anaemia adverse reactions was 22.8% (CTCAE grade ≥3 7.4%).

Patient-reported outcome (PRO) data indicate no difference for the olaparib-treated patients as compared to placebo as measured by improvement and worsening rates in the TOI and FACT-O total.

gBRCA1/2-mutated HER2-negative metastatic breast cancer

OlympiAD (Study D0819C00003)

The safety and efficacy of olaparib in patients with gBRCA1/2-mutations who had HER2-negative metastatic breast cancer were studied in a Phase III randomised, open-label, controlled trial (OlympiAD). In this study 302 patients with a documented deleterious or suspected deleterious gBRCA mutation were randomised 2:1 to receive either Lynparza (300 mg [2 × 150 mg tablets] twice daily) or physician’s choice of chemotherapy (capecitabine 42%, eribulin 35%, or vinorelbine 17%) until progression or unacceptable toxicity. Patients with BRCA1/2 mutations were identified from germline testing in blood via a local test or by central testing at Myriad. Patients were stratified based on: receipt of prior chemotherapy regimens for metastatic breast cancer (yes/no), hormone receptor (HR) positive vs triple negative (TNBC), prior platinum treatment for breast cancer (yes/no). The primary endpoint was PFS assessed by blinded independent central review (BICR) using RECIST 1.1. Secondary endpoints included PFS2, OS, objective response rate (ORR) and HRQoL.

Patients must have received treatment with an anthracycline unless contraindicated and a taxane in either a (neo)adjuvant or metastatic setting. Patients with HR+ (ER and/or PgR positive) tumours must have received and progressed on at least one endocrine therapy (adjuvant or metastatic) or had disease that the treating physician believed to be inappropriate for endocrine therapy. Prior therapy with platinum was allowed in the metastatic setting provided there had been no evidence of disease progression during platinum treatment and in the (neo)adjuvant setting provided the last dose was received at least 12 months prior to randomisation. No previous treatment with a PARP inhibitor, including olaparib, was permitted.

Demographic and baseline characteristics were generally well balanced between the olaparib and comparator arms (see Table 7).

Table 7. Patient demographic and baseline characteristics in OlympiAD:

As subsequent therapy, 0.5% and 8% of patients received a PARP inhibitor in the treatment and comparator arms, respectively; 29% and 42% of patients, respectively, received subsequent platinum therapy.

A statistically significant improvement in PFS, the primary efficacy outcome, was demonstrated for olaparib-treated patients compared with those in the comparator arm (see Table 8 and Figure 6).

Table 8. Summary of key efficacy findings for patients with gBRCA1/2-mutated HER2-negative metastatic breast cancer in OlympiAD:

^a Based on stratified log-rank test.
^b Post-hoc analysis.
^c The median follow-up time in censored patients was 25.3 months for olaparib versus 26.3 months for comparator.
^d Confirmed responses (by BICR) were defined as a recorded response of either CR/PR, confirmed by repeat imaging not less than 4 weeks after the visit when the response was first observed. In the olaparib arm 8% with measurable disease had a complete response versus 1.5% of patients in the comparator arm; 74/167 (44%) of patients in the olaparib arm had a partial response versus 14/66 (21%) of patients in the chemotherapy arm. In the TNBC patient subgroup the confirmed ORR was 48% (41/86) in the olaparib arm and 12% (4/33) in the comparator arm. In the HR+ patient subgroup the confirmed ORR was 57% (46/81) in the olaparib arm and 33% (11/33) in the comparator arm.
^bd Twice daily; CI Confidence interval; DOR Duration of response; DCO Data cut off; HR Hazard ratio; HR+ Hormone receptor positive, ORR Objective response rate; OS overall survival; PFS progression-free survival; PFS2 Time to second progression or death, TNBC triple negative breast cancer.

Figure 6. OlympiAD: Kaplan-Meier plot of BICR PFS in patients with gBRCA1/2-mutated HER2-negative metastatic breast cancer (77% maturity) DCO 09 December 2016:

Consistent results were observed in all predefined patient subgroups (see Figure 7). Subgroup analysis indicated PFS benefit of olaparib versus comparator in TNBC (HR 0.43; 95% CI: 0.29-0.63, n=152) and HR+ (HR 0.82; 95% CI: 0.55-1.26, n=150) patient subgroups.

Figure 7. PFS (BICR), Forest plot, by prespecified subgroup:

In a post-hoc analysis of the subgroup of patients that had not progressed on chemotherapy other than platinum, the median PFS in the olaparib arm (n=22) was 8.3 months (95% CI 3.1-16.7) and 2.8 months (95% CI 1.4-4.2) in the chemotherapy arm (n=16) with a HR of 0.54 (95% CI 0.24-1.23). However, the number of patients is too limited to make meaningful conclusions on the efficacy in this subgroup.

Seven male patients were randomised (5 olaparib and 2 comparator). At the time of the PFS analysis, 1 patient had a confirmed partial response with a duration of response of 9.7 months in the olaparib arm. There were no confirmed responses in the comparator arm.

Figure 8. OlympiAD: Kaplan-Meier plot of OS in patients with gBRCA1/2-mutated HER2-negative metastatic breast cancer (64% maturity) DCO 25 September 2017:

OS analysis in patients with no prior chemotherapy for metastatic breast cancer indicated benefit in these patients with a HR of 0.45 (95% CI 0.27-0.77), while for further lines of therapy HR exceeded 1.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Lynparza in all subsets of the paediatric population, in ovarian carcinoma (excluding rhabdomyosarcoma and germ cell tumours) (see section 4.2 for information on paediatric use).