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PHARMACOLOGY: 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), 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 HR-deficient cancer cells, the repair of these DNA DSBs is impaired. Cancer cells can become HR deficient due to inactivation of genes with a direct or indirect role in HRR, such as BRCA1/2, ATM, CDK12 and others. 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 deleterious mutations in key HRR genes, 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 x 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 1 and Figures 1 and 2. (See Table 1, Figures 1 and 2.)
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Click on icon to see table/diagram/imageConsistent 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 x 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 2 and Figure 3. (See Table 2 and Figure 3.)
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Click on icon to see table/diagram/imageAt the final analysis of OS (61% maturity) the HR was 0.74 (95% CI 0.54-1.00; p=0.0537; median 51.7 months for olaparib vs 38.8 months for placebo) which did not reach statistical significance. The secondary endpoints TFST and PFS2 demonstrated a persistent and statistically significant improvement for olaparib compared with placebo. Results for OS, TFST and PFS2 are presented in Table 3 and Figure 4. (See Table 3 and Figure 4.)
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Click on icon to see table/diagram/imageAmong 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: 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 x 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 BRCA1/2 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 3 and for all patients in Study 19 in Table 4 and Figure 5. (See Table 4 and Figure 5.)
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Click on icon to see table/diagram/imageA 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 5 and for all patients in Study 19 in Table 5 and Figure 6. (See Table 5 and Figure 6.)
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Click on icon to see table/diagram/imageAt 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.
First-line maintenance treatment of advanced ovarian cancer: PAOLA-1 was a Phase III randomised, double-blind, placebo-controlled, multicentre trial that compared the efficacy of Lynparza (300 mg [2 x 150 mg tablets] twice daily) in combination with bevacizumab (15 mg/kg of body weight given once every 3 weeks as an intravenous infusion) compared with placebo plus bevacizumab for the maintenance treatment of newly-diagnosed advanced (FIGO Stage III-IV) high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer.
The study randomised 806 patients (2:1 randomisation: 537 olaparib/bevacizumab: 269 placebo/bevacizumab) who had no evidence of disease (NED) due to complete surgical resection, or who were in complete response (CR), or partial response (PR) following completion of first-line platinum-containing chemotherapy and bevacizumab. Patients were stratified by first-line treatment outcome (timing and outcome of cytoreductive surgery and response to platinum-based chemotherapy) and tBRCAm status, determined by prospective local testing. Patients continued bevacizumab in the maintenance setting and started treatment with Lynparza after a minimum of 3 weeks and up to a maximum of 9 weeks following completion of their last dose of chemotherapy. Treatment with Lynparza was continued for up to 2 years or until progression of the underlying disease. Patients who in the opinion of the treating physician could derive further benefit from continuous treatment could be treated beyond 2 years. Treatment with bevacizumab was for a total of up to 15 months, including the period given with chemotherapy and given as maintenance.
Demographic and baseline characteristics were well balanced between both arms. The median age of patients was 61 years overall. Most patients in both arms were ECOG performance status 0 (70%). Ovarian cancer was the primary tumour in 86% of the patients. The most common histological type was serous (96%) and endometrioid histology was reported in 2% of the patients. Most patients were diagnosed in FIGO stage IIIC (63%). All patients had received first-line platinum-based therapy and bevacizumab. Patients were not restricted by the surgical outcome with 65% having complete cytoreduction at initial or interval debulking surgery and 35% having residual macroscopic disease.
The median duration of treatment with Lynparza was 17.3 months and 15.6 months for placebo. The median duration of bevacizumab post-randomisation was 11.0 months on the Lynparza arm and 10.4 months on the placebo arm. (See Table 6.)
Click on icon to see table/diagram/imageThe 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 first subsequent anti-cancer therapy or death (TFST) and health related quality of life (HRQoL). Patients had RECIST 1.1 tumour assessments at baseline and every 24 weeks (CT/MRI at 12 weeks if clinical or CA 125 progression) for up to 42 months or until objective radiological disease progression.
The study demonstrated a clinically meaningful and statistically significant improvement in investigator assessed PFS for olaparib/bevacizumab compared to placebo/bevacizumab. The investigator assessment of PFS was supported with a BICR of PFS (HR 0.63; 95% CI 0.51-0.77, p<0.0001 with a median of 26.1 months for olaparib/bevacizumab vs 18.3 months for placebo/bevacizumab). At the time of the PFS analysis, the PFS2 data were 39% mature, however, the point estimate of HR favoured olaparib. Although not controlled for multiplicity, there was a clinically meaningful delay in TFST observed for olaparib-treated patients. At the time of PFS analysis, interim OS data were 26% mature with events reported in a similar proportion of patients in both arms. (See Table 7 and Figure 7.)
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Click on icon to see table/diagram/imageOverall, HRQoL remained stable across the 24-month treatment period in patients receiving olaparib or placebo in combination with bevacizumab. There was no clinically meaningful difference in mean change from baseline of the EORTC QLQ-C30 global health status/QoL score for olaparib/bevacizumab-treated patients compared with placebo/bevacizumab-treated patients (estimated difference 0.59, 95% CI -1.40 - 2.57, p=0.5626).
gBRCA1/2-mutated HER2-negative metastatic breast cancer: OlympiAD: 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 x 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 8).
Click on icon to see table/diagram/imageAs 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 9 and Figure 8).
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Click on icon to see table/diagram/imageConsistent results were observed in all predefined patient subgroups (see Figure 9). 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. (See Figure 9.)
Click on icon to see table/diagram/imageIn 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. (See Figure 10.)
Click on icon to see table/diagram/imageOS 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.
Maintenance following first-line treatment of germline BRCA-mutated metastatic adenocarcinoma of the pancreas: POLO Study: POLO was a Phase III, randomised, double-blind, placebo-controlled, multicentre trial that compared the efficacy of Lynparza maintenance treatment (300 mg [2 x 150 mg tablets] twice daily) with placebo in gBRCA-mutated metastatic adenocarcinoma of the pancreas. The study randomised 154 patients (3:2 randomisation: 92 olaparib and 62 placebo) whose disease had not progressed following at least 16 weeks of first-line platinum-based chemotherapy. There was no upper limit to the duration of chemotherapy received. After 16 weeks of continuous platinum-based chemotherapy, the platinum could be discontinued at any time for toxicity and the other agents continued; the patients were eligible for randomisation as long as there was no evidence of progression at any time during chemotherapy treatment. All toxicities from previous anti-cancer therapy must have been resolved to CTCAE grade 1, except for alopecia, grade 3 peripheral neuropathy and Hgb ≥ 9 g/dL. Lynparza treatment was continued until progression of the underlying disease.
Patients with germline BRCA mutations were identified from prior local testing results or by central testing using the Myriad BRACAnalysis or Myriad BRACAnalysis CDx test. The BRCAm status of all patients identified using prior local testing results was confirmed, where sent, using the Myriad BRACAnalysis or Myriad BRACAnalysis CDx test.
Demographic and baseline characteristics were generally well balanced between the olaparib and placebo arms. Median age was 57 years in both arms; 30% of patients in the olaparib arm were ≥ 65 years compared to 21% in the placebo arm. Fifty-eight per-cent (58%) of patients were male. Most patients were ECOG performance status 0 (67%). Ninety-six per-cent (96%) of patients were randomised within 8 weeks of their last dose of platinum-based chemotherapy. The median time from initiation of first-line platinum-based chemotherapy to randomisation was 5.8 months (range 3.4 to 33.4 months) and 49% of patients were in complete or partial response to their most recent platinum-based regimen.
The primary endpoint was progression-free survival (PFS), defined as time from randomisation to progression determined by BICR using modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, or death. Secondary efficacy endpoints included overall survival (OS), time from randomisation to second progression or death (PFS2), time from randomisation to first subsequent anti-cancer therapy or death (TFST), time from randomisation to discontinuation of treatment or death (TDT), objective response rate (ORR), duration of response (DoR), response rate, time to response and health related quality of life (HRQoL). Patients had tumour assessments at baseline and every 8 weeks for 40 weeks, and then every 12 weeks relative to the date of randomisation, until objective radiological disease progression. For PFS, the median follow-up time for censored patients was 9.1 months in the olaparib arm and 3.8 months in the placebo arm. For OS, the median follow-up time for censored patients was 31.3 months in the olaparib arm and 23.9 months in the placebo arm.
The study demonstrated a clinically meaningful and statistically significant improvement in PFS for olaparib compared to placebo, with a HR of 0.53 (95% CI 0.35 - 0.82; p=0.0038; the median was 7.4 months for olaparib vs 3.8 months for placebo). The sensitivity analysis of PFS by investigator assessment (HR 0.51; 95% CI 0.34 to 0.78; p=0.0017; median 6.3 months vs 3.7 months for olaparib vs placebo, respectively) was consistent with the PFS analysis by BICR. Based on Kaplan-Meier estimates, the proportion of patients that were alive and progression-free at 12, 24 and 36 months were 34%, 28% and 22% for olaparib vs 15%, 10% and 10% for placebo.
At the time of PFS analysis the median DoR was longer in the olaparib arm (24.9 months) compared to the placebo arm (3.7 months), with a longer median time to onset of response (5.4 months for olaparib vs 3.6 months for placebo).
At the final analysis of OS (70% maturity) the HR for OS was 0.83 (95% CI 0.56 to 1.22; p=0.3487; median 19.0 months for olaparib vs 19.2 months for placebo) which did not reach statistical significance. The percentage of patients that were alive and in follow-up were 28% in the olaparib arm and 18% in the placebo arm.
At the time of final OS analysis, the HR for PFS2 (60% maturity, not controlled for multiplicity) was 0.66 (95% CI 0.42 - 1.02; p=0.0613) with a difference in median of 7.6 months in favour of olaparib (median 16.9 months for olaparib vs 9.3 months for placebo). A clinically meaningful and statistically significant improvement in TFST and TDT was observed for olaparib-treated patients. (See Table 10, Figures 11 and 12.)
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Click on icon to see table/diagram/imagePatient-reported HRQoL was assessed using the EORTC QLQ-C30 and its pancreatic cancer module (EORTC QLQ-PAN26). A 10-point change was pre-defined as clinically meaningful on a 0-100 points global HRQoL scale. The adjusted mean change from baseline in global HRQoL score across all timepoints up to 6 months was -1.20 ± 1.42 in the olaparib group (n=84) and 1.27 ± 1.95 in the placebo group (n=54), with a corresponding estimated difference of -2.47 points (95% CI, -7.27 to 2.33), demonstrating no worsening in olaparib treated patients and no clinically meaningful differences in global HRQoL over the treatment period between arms. Median time to clinically meaningful deterioration (≥10 points decrease from baseline sustained at the next timepoint) in global HRQoL score was numerically longer in the olaparib arm compared to placebo (HR 0.72; 95% CI: 0.41-1.27; medians: 21.2 months olaparib vs. 6.0 months placebo). Over the treatment period, the proportion of patients with clinically significant improvement (≥10 points increase from baseline) in global HRQoL score was 29.2% in the olaparib arm and 22.4% in the placebo arm.
Homologous recombination repair gene mutated metastatic castration-resistant prostate cancer: PROfound Study: PROfound was a Phase III randomised, open-label, multicentre trial that evaluated the efficacy of Lynparza (300 mg [2 x 150 mg tablets] twice daily) versus a comparator arm of investigator's choice of NHA ([new hormonal agent] enzalutamide or abiraterone acetate) in men with metastatic castration-resistant prostate cancer (mCRPC). Patients needed to have progressed on prior NHA for the treatment of metastatic prostate cancer and/or CRPC and have a tumour mutation in one of 15 genes involved in the homologous recombination repair (HRR) pathway.
Patients were divided into two cohorts based on HRR gene mutation status. Patients with mutations in either BRCA1, BRCA2 or ATM were randomised in Cohort A; patients with mutations among 12 other genes involved in the HRR pathway (BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D or RAD54L) were randomised in Cohort B. Patients with co-mutations (BRCA1, BRCA2 or ATM plus a Cohort B gene) were randomised in Cohort A. Although patients with PPP2R2A gene mutations were enrolled in the trial, Lynparza is not indicated for the treatment of patients with this gene mutation due to unfavourable benefit-risk.
The study randomised 387 patients (2:1 randomisation: 256 olaparib and 131 comparator); in Cohort A there were 245 patients (162 olaparib and 83 comparator) and in Cohort B there were 142 patients (94 olaparib and 48 comparator). Patients were stratified by prior taxane use and evidence of measurable disease. Treatment was continued until disease progression. Patients randomised to comparator were given the option to switch to olaparib upon confirmed radiological BICR progression.
Patients with HRR gene mutations were identified based on prostate cancer tissue specimen testing by the Foundation Medicine FoundationOne HRR clinical trial assay performed in a CLIA certified laboratory (CLIA HRR Clinical Trial Assay) or from reanalysis of data from a prior Foundation Medicine test.
Demographics and baseline characteristics were generally well balanced between the olaparib and comparator arms in Cohort A+B. Median age was 69 years in both arms. Prior therapy in the olaparib arm was 66% taxane, 40% enzalutamide, 38% abiraterone acetate and 20% both enzalutamide and abiraterone acetate. Prior therapy in the comparator arm was 63% taxane, 41% enzalutamide, 41% abiraterone acetate and 18% both enzalutamide and abiraterone acetate. Fifty-eight percent (58%) of patients in the olaparib arm and 55% in the comparator arm had measurable disease at study entry. The proportion of patients with bone, distant lymph node, locoregional lymph node, liver and respiratory metastases was 85%, 39%, 21%, 10% and 17%, respectively in the olaparib arm and 86%, 39%, 24%, 14% and 12%, respectively in the comparator arm. Most patients in both treatment arms had an ECOG of 0 or 1 (95%). Baseline pain scores (BPI-SF worst pain) were 0-<2 (48%), 2-3 (12%) or >3 (36%) in the olaparib arm and 0-<2 (44%), 2-3 (10%) or >3 (43%) in the comparator arm. Median baseline PSA was 68.22 μg/L in the olaparib arm and 106.49 μg/L in the comparator arm.
The primary endpoint of the study was radiological progression free survival (rPFS) in Cohort A determined by BICR using RECIST 1.1 (soft tissue) and Prostate Cancer Working Group (PCWG3) (bone). Key secondary endpoints included confirmed objective response rate (ORR) by BICR (Cohort A), rPFS by BICR (Cohort A+B), time to pain progression (TTPP) (Cohort A) and overall survival (OS) (Cohort A).
Other secondary endpoints in Cohort A and Cohort A+B included time to first symptomatic skeletal-related event (SSRE), duration of response (DoR), time to opiate use for cancer-related pain, confirmed soft tissue ORR, prostate specific antigen (PSA50) response, circulating tumour cells (CTC) conversion rate, time to second progression or death (PFS2) and disease-related symptoms and health related quality of life ([HRQoL], pain progression, pain severity progression, pain interference and pain palliation). Other secondary end-points in Cohort B included rPFS by BICR. In addition, other secondary end-points in Cohort B and Cohort A+B included confirmed ORR by BICR, OS and time to pain progression.
The study demonstrated a clinically meaningful and statistically significant improvement in BICR assessed rPFS for olaparib vs comparator in Cohort A and also in Cohort A+B.
In Cohort A there was a statistically significant and clinically meaningful improvement in confirmed radiological ORR by BICR for patients with measurable disease at baseline in the olaparib arm vs comparator and an improvement observed in confirmed radiological ORR Cohort A+B. There was a statistically significant and clinical meaningful delay in TTPP in the olaparib arm compared with the investigators choice of NHA arm in Cohort A and the results in Cohort A+B were consistent with Cohort A.
The final analysis of OS demonstrated a statistically significant improvement in OS in patients randomised to Lynparza compared to patients in the investigators choice of NHA arm in Cohort A. (See Table 11, Figures 13, 14 and 15.)
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Click on icon to see table/diagram/imageIn Cohort A and Cohort A+B the benefit of olaparib over investigators choice of NHA was maintained across all pre-defined subgroups, with clinically meaningful reductions in the risk of progression or death in olaparib-treated patients (ranging from 39% to 75% in Cohort A and from 23% to 88% in Cohort A+B).
In Cohort B, the median rPFS was 4.8 months for olaparib vs 3.3 months for comparator with a HR of 0.88 (95% CI 0.58, 1.36; p=0.3976 [nominal]). Two patients (3.7%) in the olaparib arm and 2 patients (8.3%) in the comparator arm with measurable disease at baseline had a confirmed radiological objective response. The odds ratio (OR) and 95% CIs were not calculated due to the small number of responders. In the olaparib arm, the 2 patients had CDK12 mutations and achieved a partial response. In the comparator arm, the 2 patients had co-occurring mutations (one with PALB2+PPP2R2A and one with CDK12+PALB2) and achieved a partial response. Stable disease was observed in 57.4% of patients in the olaparib arm and 29.2% of patients in the comparator arm. The final OS analysis had events in 100/142 patients. Median OS was 14.1 months for olaparib vs 11.5 months for comparator with a HR of 0.96 (95% CI 0.63, 1.49; p=0.7921, nominal). The HR indicates no detriment in OS for olaparib-treated patients.
With regards to the rPFS subgroup analysis by Cohort B gene, there was a trend for benefit of olaparib over comparator for patients with a single CDK12 mutation. For CHEK2, RAD54L and PPP2R2A, results should be interpreted with caution due to the small number of events. Hazard ratios were not calculable for some of the Cohort B genes (BARD1, BRIP1, CHEK1, PALB2, RAD51B, and RAD51D) due to the small number of events in these subgroups. In Cohort B a subgroup analysis of confirmed ORR for each individual gene in patients with single HRR gene mutations only, 2/34 CDK12m patients (5.9%) in the olaparib arm and no patients in the comparator arm (N=12) had a response. The OR and 95% CIs were not calculable. (See Table 12.)
Click on icon to see table/diagram/imageOlaparib improved overall adjusted mean change (based in mixed model of repeated measures analysis) from baseline scores in HRQoL (FACT-P total score, FACT-General total score, Trial Outcome Index), functioning (physical well-being, functional well-being) and prostate cancer symptoms (PCS, FACT Advanced Prostate Symptom Index-6) compared with investigators choice of NHA during treatment demonstrating that patients in the olaparib arm experienced improvement in HRQoL, functioning and prostate cancer symptoms compared with patients in the investigators choice of NHA arm in Cohort A. The analysis of adjusted mean change from baseline in HRQoL, functioning and prostate cancer symptoms scores in Cohort A were consistent with results in Cohort A+B.
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 Dosage and Administration for information on paediatric use).
Pharmacokinetics: The pharmacokinetics of olaparib at the 300 mg tablet dose are characterised by an apparent plasma clearance of ~7 L/h, an apparent volume of distribution of ~158 L and a terminal half-life of 15 hours. On multiple dosing, an AUC accumulation ratio of 1.8 was observed and PK appeared to be time-dependent to a small extent.
Absorption: Following oral administration of olaparib via the tablet formulation (2 x 150 mg), absorption is rapid with median peak plasma concentrations typically achieved 1.5 hours after dosing.
Co-administration with food slowed the rate (tmax delayed by 2.5 hours and Cmax reduced by approximately 21%) but did not significantly affect the extent of absorption of olaparib (AUC increased 8%). Consequently, Lynparza may be taken without regard to food (see Dosage & Administration).
Distribution: The in vitro plasma protein binding is approximately 82% at 10 μg/mL which is approximately Cmax.
In vitro, human plasma protein binding of olaparib was dose-dependent; the fraction bound was approximately 91% at 1 μg/mL, reducing to 82% at 10 μg/mL and to 70% at 40 μg/mL. In solutions of purified proteins, the olaparib fraction bound to albumin was approximately 56%, which was independent of olaparib concentrations. Using the same assay, the fraction bound to alpha-1 acid glycoprotein was 29% at 10 μg/mL with a trend of decreased binding at higher concentrations.
Biotransformation: In vitro, CYP3A4/5 were shown to be the enzymes primarily responsible for the metabolism of olaparib (see Interactions).
Following oral dosing of 14C-olaparib to female patients, unchanged olaparib accounted for the majority of the circulating radioactivity in plasma (70%) and was the major component found in both urine and faeces (15% and 6% of the dose, respectively). The metabolism of olaparib is extensive. The majority of the metabolism was attributable to oxidation reactions with a number of the components produced undergoing subsequent glucuronide or sulfate conjugation. Up to 20, 37 and 20 metabolites were detected in plasma, urine and faeces, respectively, the majority of them representing < 1% of the dosed material. A ring-opened piperazin-3-ol moiety, and two mono-oxygenated metabolites (each ~10%) were the major circulating components, with one of the mono-oxygenated metabolites also being the major metabolite in the excreta (6% and 5% of the urinary and faecal radioactivity, respectively).
In vitro, olaparib produced little/no inhibition of UGT2B7, or CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6 or 2E1 and is not expected to be a clinically significant time dependent inhibitor of any of these CYP enzymes. Olaparib inhibited UGT1A1 in vitro, however, PBPK simulations suggest this is not of clinical importance. In vitro, olaparib is a substrate of the efflux transporter P-gp, however, this is unlikely to be of clinical significance (see Interactions).
In vitro, data also show that olaparib is not a substrate for OATP1B1, OATP1B3, OCT1, BCRP or MRP2 and is not an inhibitor of OATP1B3, OAT1 or MRP2.
Elimination: Following a single dose of 14C-olaparib, ~86% of the dosed radioactivity was recovered within a 7-day collection period, ~44% via the urine and ~42% via the faeces. Majority of the material was excreted as metabolites.
Special populations: In population based PK analyses, patient age, gender, bodyweight, tumour location or race (including White and Japanese patients) were not significant covariates.
Renal impairment: In patients with mild renal impairment (creatinine clearance 51 to 80 ml/min), AUC increased by 24% and Cmax by 15% compared with patients with normal renal function. No Lynparza dose adjustment is required for patients with mild renal impairment.
In patients with moderate renal impairment (creatinine clearance 31 to 50 ml/min), AUC increased by 44% and Cmax by 26% compared with patients with normal renal function. Lynparza dose adjustment is recommended for patients with moderate renal impairment (see Dosage & Administration).
There are no data in patients with severe renal impairment or end-stage renal disease (creatinine clearance <30 ml/min).
Hepatic impairment: In patients with mild hepatic impairment (Child-Pugh classification A), AUC increased by 15% and Cmax by 13% and in patients with moderate hepatic impairment (Child-Pugh classification B), AUC increased by 8% and Cmax decreased by 13% compared with patients with normal hepatic function. No Lynparza dose adjustment is required for patients with mild or moderate hepatic impairment (see Dosage & Administration). There are no data in patients with severe hepatic impairment (Child-Pugh classification C).
Paediatric population: No studies have been conducted to investigate the pharmacokinetics of olaparib in paediatric patients.
Toxicology: Preclinical safety data: Genotoxicity: Olaparib showed no mutagenic potential, but was clastogenic in mammalian cells in vitro. When dosed orally to rats, olaparib induced micronuclei in bone marrow. This clastogenicity is consistent with the known pharmacology of olaparib and indicates potential for genotoxicity in man.
Repeat-dose toxicity: In repeat-dose toxicity studies of up to 6 months duration in rats and dogs, daily oral doses of olaparib were well-tolerated. The major primary target organ for toxicity in both species was the bone marrow, with associated changes in peripheral haematology parameters. These changes were reversible within 4 weeks of cessation of dosing. In rats, minimal degenerative effects on gastrointestinal tract were also noted. These findings occurred at exposures below those seen clinically. Studies using human bone marrow cells also showed that direct exposure to olaparib can result in toxicity to bone marrow cells in ex vivo assays.
Reproductive toxicology: In a female fertility study where rats were dosed until implantation, although extended oestrus was observed in some animals, mating performance and pregnancy rate was not affected. However, there was a slight reduction in embryofoetal survival.
In rat embryofoetal development studies, and at dose levels that did not induce significant maternal toxicity, olaparib caused reduced embryofoetal survival, reduced foetal weight and foetal developmental abnormalities, including major eye malformations (e.g. anophthalmia, microphthalmia), vertebral/rib malformation and visceral and skeletal abnormalities.
Carcinogenicity: Carcinogenicity studies have not been conducted with olaparib.
