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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 or new hormonal agents (NHA).
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 cancer cells lacking critical functional components for efficient HRR such as BRCA1 or 2, DNA DSBs cannot be repaired accurately or effectively, leading to substantial homologous recombination deficiency (HRD). Instead, alternative and error-prone pathways are activated, such as the classical non-homologous end joining (NHEJ) pathway, leading to a high degree of 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. 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 possibly 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.
Combined anti-tumour effect with NHAs: Pre-clinical studies in prostate cancer models reported a combined anti-tumour effect when PARP inhibitors and next-generation hormonal agents are administered together. PARP is involved in positive co-regulation of androgen receptor (AR) signalling, which leads to enhanced AR target gene suppression when PARP/AR signalling is co-inhibited. Other pre-clinical studies reported that treatment with NHAs inhibit the transcription of some HRR genes, therefore, inducing HRR deficiency and increased sensitivity to PARP inhibitors via non-genetic mechanisms.
Detection of BRCA1/2 mutations: Genetic testing should be conducted by an experienced laboratory using a validated test. Local or central testing of blood and/or tumour samples for germline and/or somatic BRCA1/2 mutations have been used in different studies. DNA obtained from a tissue or blood sample has been tested in most of the studies, with testing of ctDNA being used for exploratory purposes. 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. Homologous recombination deficiency (HRD) positive status can be defined by detection of a BRCA1/2 mutation classified as deleterious/suspected deleterious or pathogenic/likely pathogenic. Detection of these mutations could be combined with positive HRD score (below) to determine HRD positive status.
Detection of genomic instability: HR deficiency-associated genomic alterations that have been investigated in PAOLA-1 include genome-wide loss of heterozygosity, telomeric allelic imbalance and large scale transition, which are continuous measures with pre-defined criteria and score. Composite genomic instability score (GIS, also called HRD score) is determined when the combined measures and respective scores are used to assess the extent of specific genomic aberrations accumulated in tumour cells. Lower score defines lower likelihood of HR deficiency of tumour cells and higher score determines higher likelihood of HR deficiency of tumour cells at the time of the sample collection relative to exposure to DNA damaging agents. Validated cut-offs should be used to determine GIS positive status.
HRD positive status can be defined by a composite GIS score for HR deficiency-associated genomic alterations tested 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 Tumours (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 and 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 (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 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 4 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.
OPINION Study: OPINION, a Phase IIIb single arm, multicentre study, investigated olaparib as a maintenance treatment in patients with PSR ovarian, fallopian tube or primary peritoneal cancer following 2 or more lines of platinum based chemotherapy and who did not have a known deleterious or suspected deleterious gBRCA mutation. Patients whose disease was in response (CR or PR) following completion of platinum-based chemotherapy were enrolled. A total of 279 patients were enrolled and received olaparib treatment in this study until disease progression or unacceptable toxicity. Based on central testing 90.7% were confirmed with a non gBRCAm status, in addition 9.7% were identified as sBRCAm.
The primary endpoint was investigator-assessed PFS according to modified RECIST v1.1. Secondary endpoints included OS.
Olaparib, when used as maintenance therapy, demonstrated clinical activity in patients with non-gBRCAm PSR ovarian cancer. At the time of primary PFS analysis, the OS data were 30% mature.
A summary of the primary objective outcome for patients with non-gBRCAm PSR ovarian cancer in OPINION is presented in Table 6. (See Table 6.)
Click on icon to see table/diagram/imageFirst-line maintenance treatment of HRD positive advanced ovarian cancer: PAOLA-1 Study: PAOLA-1 was a Phase III randomised, double-blind, placebo-controlled, multicentre trial that compared the efficacy and safety 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) versus placebo plus bevacizumab for the maintenance treatment of advanced (FIGO Stage III-IV) high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer following first-line platinum-based chemotherapy and bevacizumab. Treatment with bevacizumab was for a total of up to 15 months/22 cycles, including the period given with chemotherapy and given as maintenance.
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 had completed a minimum of 4 and a maximum of 9 cycles, with the majority (63%) having received 6 cycles of first line platinum-taxane based chemotherapy, including a minimum of 2 cycles of bevacizumab in combination with the 3 last cycles of chemotherapy. The median number of bevacizumab cycles prior to randomisation was 5.
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 until progression of the underlying disease, unacceptable toxicity or for up to 2 years. Patients who in the opinion of the treating physician could derive further benefit from continuous treatment could be treated beyond 2 years.
Demographic and baseline characteristics were balanced between both arms in the ITT population and in the biomarker-defined sub-groups by tBRCAm (prospectively and retrospectively defined), GIS and HRD status (defined in this study by a combination of both biomarkers). 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 63% having complete cytoreduction at initial or interval debulking surgery and 37% having residual macroscopic disease. Thirty percent (30%) of patients in both arms were tBRCAm at screening. Demographic and baseline characteristics in the biomarker sub-groups were consistent with those in the ITT population. In the HRD-positive subgroup, 65% of patients had complete cytoreduction and 35% of patients had residual macroscopic disease. In the overall patient population enrolled, 30% of patients in both arms were tBRCAm (deleterious/pathogenic mutation) at screening by local testing and for 4% of patients the BRCAm status was unknown. Retrospective analysis of available clinical samples was conducted in 97% of patients to confirm tBRCAm status and investigate genomic instability score as described above. Among non-tBRCAm patients, 29% (19% of the overall population) had positive GIS pre-defined in this study as composite score ≥42. When tBRCAm status and positive GIS were combined, patients with HRD-positive, HRD-negative and HRD unknown status in their tumours represented 48%, 34% and 18% of the overall patient population.
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 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 met its primary end-point in the ITT population demonstrating a statistically significant improvement in investigator assessed PFS for olaparib/bevacizumab compared to placebo/bevacizumab (HR 0.59, 95% CI 0.49-0.72, p<0.0001 with a median of 22.1 months for olaparib/bevacizumab vs 16.6 months for placebo/bevacizumab). This was consistent with a BICR analysis of PFS. However, patients defined as biomarker-positive (tBRCAm, GIS, HRD status positive defined as tBRCAm and/or GIS positive) derived most of the benefit.
Final analysis of PFS2 (DCO 22 March 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 vs 32.6 months for placebo/bevacizumab). Overall survival data were immature in the overall population and biomarker subgroups. Sixty percent (60%) of patients in the olaparib/bevacizumab arm and 74% in the placebo/bevacizumab arm received subsequent therapy and of these patients, 20% and 47% in the olaparib/bevacizumab and placebo/bevacizumab arms, respectively, received a PARP inhibitor.
In the tBRCAm as randomised subgroup (241/806 patients) median PFS for the olaparib/bevacizumab arm was 37.2 months vs 22.0 months for the placebo/bevacizumab arm (HR=0.34, 95% CI 0.23, 0.51) and for OS (DCO 22 March 2020) the HR was 0.68 (95% CI 0.40, 1.19).
Efficacy results in other biomarkers subgroup analyses based on retrospectively analysed tumour samples are presented in Table 7. (See Table 7.)
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Click on icon to see table/diagram/imageAdjuvant treatment of BRCA-mutated HER2-negative high risk early breast cancer: The efficacy of Lynparza was investigated in a randomised, double-blind, parallel group, placebo-controlled, multicentre study in patients with germline BRCA1/2 mutations and HER2-negative high risk early breast cancer (OlympiA). VIOLETTE was a Phase II, open-label, multicentre study investigating the efficacy of agents targeting DNA damage repair in combination with olaparib versus olaparib monotherapy in the treatment of second or third line metastatic TNBC patients, including patients with somatic BRCAm tumours.
OlympiA study in HER2-negative high risk early breast cancer patients with a germline BRCA mutation: OlympiA was a Phase III randomised, double-blind, parallel group, placebo-controlled, multicentre study to assess the efficacy and safety of olaparib (300 mg [2 x 150 mg tablets] twice daily) vs placebo as adjuvant treatment in patients with germline BRCA1/2 mutations and HER2-negative high risk early breast cancer who had completed definitive local treatment and neoadjuvant or adjuvant chemotherapy. Patients were required to have completed at least 6 cycles of neoadjuvant or adjuvant chemotherapy containing anthracyclines, taxanes or both. Prior platinum for previous cancer (e.g. ovarian) or as adjuvant or neoadjuvant treatment for breast cancer was allowed. High risk early breast cancer patients were defined as follows: patients who have received prior neoadjuvant chemotherapy (both TNBC and ER and/or PgR positive patients) must have had residual invasive cancer in the breast and/or the resected lymph nodes (non-pCR) and additionally ER and/or PgR positive patients must have had a CPS&EG score of ≥3.
patients who have received prior adjuvant chemotherapy: triple negative breast cancer (TNBC) patients must have had node positive disease or node negative disease with a ≥pT2 primary tumor; ER and/or PgR positive, HER2-negative patients must have had ≥4 pathologically confirmed positive lymph nodes.
Patients were randomised in a 1:1 ratio to either olaparib (n=921) or placebo (n=915). Randomisation was stratified by hormone receptor status (ER and/or PgR positive/ HER2 negative versus TNBC), by prior neoadjuvant versus adjuvant chemotherapy, and by prior platinum use for breast cancer (yes versus no). Treatment was continued for 1 year, or until disease recurrence, or unacceptable toxicity. Patients with HR positive (ER and/or PgR positive) tumours also received endocrine therapy.
The primary endpoint was invasive disease free survival (IDFS), defined as the time from randomisation to date of first recurrence, where recurrence is defined as loco-regional, distant recurrence, contralateral invasive breast cancer, new cancer or death from any cause. Secondary objectives included OS, distant disease free survival [(DDFS, defined as the time from randomisation until evidence of first distant recurrence of breast cancer), the incidence of new primary contralateral breast cancers (invasive and non-invasive), new primary ovarian cancer, new primary fallopian tube cancer and new primary peritoneal cancer], and patient reported outcomes using the FACIT-Fatigue and EORTC QLQ-C30 questionnaires.
Central testing with Myriad BRACAnalysis or local gBRCA testing, if available, was used to establish study eligibility. Patients enrolled based on local gBRCA test results provided a sample for retrospective confirmatory testing with BRACAnalysis (excluding patients enrolled in China). Out of 1836 patients enrolled into OlympiA, 1539 were confirmed as gBRCAm by Myriad BRACAnalysis, either prospectively or retrospectively.
Demographic and baseline characteristics were well balanced between arms. The median age was 42 years. Sixty-seven percent (67%) of patients were White, 29% Asian and 2.6% Black. Two patients (0.2%) in the olaparib arm and four patients (0.4%) in the placebo arm were male. Sixty-one percent (61%) of patients were pre-menopausal. Eighty-nine percent (89%) of patients were ECOG performance status 0 and 11% ECOG PS 1. Eighty-two percent (82%) of patients had TNBC and 18% had hormone receptor-positive disease (defined as ER positive and/or PgR positive). Fifty percent (50%) of patients had received prior neoadjuvant and 50% received prior adjuvant chemotherapy. Ninety-four percent (94%) of patients received anthracycline and taxane. Twenty-six (26%) of patients overall had received prior platinum for breast cancer.
The study demonstrated a statistically significant and clinically meaningful improvement in IDFS in the olaparib arm compared with the placebo arm. Two hundred and eighty-four (284) patients had IDFS events, this represented 12% of patients in the olaparib arm (distant 8%, local/regional 1.4%, contralateral invasive breast cancer 0.9%, non-breast second primary malignancies 1.2%, death 0.2%) and 20% of patients in the placebo arm (distant 13%, local/regional 2.7%, contralateral invasive breast cancer 1.3%, non-breast second primary malignancies 2.3%, death 0%). A statistically significant and clinically meaningful improvement in DDFS in the olaparib arm compared with the placebo arm was also observed.1 Interim overall survival (8% maturity) did not meet statistical significance.
Efficacy results from the FAS are presented in Table 8 and for the subgroups by stratification factors in Table 9. (See Tables 8 and 9, and Figures 8, 9 and 10).
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Click on icon to see table/diagram/imageThe patient reported outcome assessments included the FACIT-fatigue (to assess fatigue and its impact upon daily activities and function) and the EORTC QLQ-C30 (to assess global health status/QoL, functioning and GI symptoms) which were completed at baseline prior to randomisation and every 6 months after randomisation for a period of 2 years. A 3-point difference in FACIT-fatigue score and a 10-point difference in EORTC QLQ-C30 scores were considered clinically meaningful. Patient reported outcome data indicate no clinically meaningful differences among olaparib-treated patients as compared to placebo when measured using FACIT-Fatigue and EORTC QLQ-C30 global health status/QoL and functioning scales. Olaparib-treated patients had worse EORTC QLQ-C30 nausea/vomiting scores during the initial assessments (at 6 and 12 months) which returned to baseline levels and were comparable to placebo-treated patients at the later assessments (18 and 24 months).
VIOLETTE study in metastatic triple negative breast cancer: VIOLETTE was a Phase II, open-label, multicentre study to assess the safety and efficacy of agents targeting DNA damage repair in combination with olaparib versus olaparib monotherapy in the treatment of second or third line metastatic TNBC patients stratified by alterations in HRR-related genes (including BRCA1/2). All patients must have received treatment with an anthracycline and/or taxane unless contraindicated, in either the neoadjuvant, adjuvant or metastatic setting. Prior therapy with platinum for metastatic breast cancer was allowed provided there was been no evidence of disease progression during platinum treatment.
All patients provided a tumour sample from either primary tumour or metastatic biopsy for tissue-based HRR gene panel testing. The tumour sample was prospectively tested for mutations in 15 pre-specified HRR genes. If the tumour test results indicated that the patient had a qualifying mutation in BRCA1 or BRCA2, the patient was eligible for olaparib monotherapy (stratum A).
Thirty-six patients with tBRCAm were enrolled to the olaparib monotherapy arm. Confirmed responses were reported in 11 of 33 patients receiving olaparib monotherapy (ORR, 33% CI 18-52%); median PFS was 6.1 months (95% CI, 5.1 to 8.9 months). Four patients had somatic BRCAm tumours and 2 out of 4 (50%) had confirmed responses on olaparib.
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 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 10).
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 11 and Figure 11).
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Click on icon to see table/diagram/imageConsistent results were observed in all predefined patient subgroups (see Figure 8). 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 12.)
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 13.)
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: The safety and efficacy of olaparib as maintenance therapy were studied in a randomised (3:2), double-blind, placebo-controlled, multicentre trial in 154 patients with germline BRCA1/2 mutations who had metastatic adenocarcinoma of the pancreas. Patients received either Lynparza 300 mg (2 x 150 mg tablets) twice daily (n=92) or placebo (n=62) until radiological disease progression or unacceptable toxicity. Patients should have not progressed during first-line platinum-based chemotherapy and should have received a minimum of 16 weeks of continuous platinum treatment, which could be discontinued at any time thereafter for unacceptable toxicity while the remaining agents continued according to the planned regimen or unacceptable toxicity for other component(s). Patients who could tolerate complete platinum-containing chemotherapy regimen until progression have not been considered for this study. The maintenance therapy was started 4 to 8 weeks after the last dose of first-line chemotherapy component(s) in the absence of progression and if all toxicities from previous anti-cancer therapy had been resolved to CTCAE grade 1, except for alopecia, grade 3 peripheral neuropathy and Hgb ≥ 9 g/dL.
Thirty-one percent (31%) of patients with germline BRCA1/2 mutations were identified from prior local testing results and 69% of patients by central testing. In the olaparib arm, 32% of patients carried a germline BRCA1 mutation, 64% a germline BRCA2 mutation and 1% carried both germline BRCA1 and germline BRCA2 mutations. In the placebo arm, 26% of patients carried a germline BRCA1 mutation, 73% a germline BRCA2 mutation and no patients carried both germline BRCA1 and germline BRCA2 mutations. The BRCAm status of all patients identified using prior local testing results was confirmed, where sent, by central testing. Ninety-eight percent (98%) of patients carried a deleterious mutation and 2% carried a suspected deleterious mutation. Large rearrangements in the BRCA1/2 genes were detected in 5.2 % (8/154) of the randomised patients.
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 20% in the placebo arm. Fifty-eight per-cent (58%) of patients in the olaparib arm and 50% of patients in the placebo arm were male. In the olaparib arm 89% of patients were White and 11% were non-White; in the placebo arm 95% of patients were White and 5% were non-White. Most patients were ECOG performance status 0 (71% in the olaparib arm and 61% in the placebo arm). Overall, the sites of metastasis prior to chemotherapy were liver 72%, lung 10% and other sites 50%. The median time from original diagnosis to randomisation across both arms was 6.9 months (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% of patients received other chemotherapy regimens. Duration of the first-line chemotherapy for metastatic disease was 4 to 6 months, >6 to <12 months and ≥12 months, respectively, in 77%, 19% and 4% of patients in the olaparib arm and in 80%, 17% and 3% in the placebo arm, with around 1 month from the last dose of the first-line chemotherapy component(s) to the start of study treatment in both arms. As best response on first-line chemotherapy, 7% of olaparib patients and 5% of placebo patients had a complete response, 44% of olaparib patients and 44% of placebo patients had a partial response and 49% of olaparib and 50% of placebo patients had stable disease. At randomisation, measurable disease was reported in 85% and 84% of patients in the olaparib or placebo arms, respectively. The median time from initiation of the first-line platinum-based chemotherapy to randomisation was 5.7 months (range 3.4 to 33.4 months).
At the time of PFS analysis, 33% of patients in the olaparib arm and 13% on the placebo arm remained on study treatment. Forty-nine percent of patients (49%) in the olaparib arm and 74% in the placebo arm received subsequent therapy. Forty-two percent (42%) of patients in the olaparib arm and 55% in the placebo arm received platinum as subsequent therapy. One percent (1%) of patients in the olaparib arm and 15% in the placebo arm received PARP inhibitor as subsequent therapy. Of the 33 (36%) and 28 (45%) of patients who received a first subsequent platinum-containing therapy, in the olaparib and placebo arms, stable disease was reported in 8 vs 6 patients, whereas 1 vs 2 patients had responses, respectively.
The primary endpoint was progression-free survival (PFS), defined as time from randomisation to progression determined by BICR using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 modified to assess patients with no evidence of disease, 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), 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 for olaparib compared to placebo (Table 12). The BICR assessment of PFS was consistent with an investigator assessment.
At final analysis of OS, the percentage of patients that were alive and in follow-up was 28% in the olaparib arm and 18% in the placebo arm. (See Table 12, Figures 14 and 15.)
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Click on icon to see table/diagram/imageTreatment of HRR Mutation Positive Metastatic Castration Resistant Prostate Cancer (mCRPC) PROfound: The efficacy of Lynparza (olaparib tablets) in the treatment of patients with homologous recombination repair (HRR)-mutated (germline and/or somatic) metastatic castration-resistant prostate cancer (mCRPC) following prior treatment with a new hormonal agent (NHA, enzalutamide or abiraterone acetate) was investigated in PROfound, a randomized, open-label, multicentre phase III trial. The study randomized 387 patients (2:1 randomization: 256 Lynparza and 131 Investigator's Choice of NHA) who had progressed on a prior NHA and had a tumour mutation in one of 15 genes involved in the HRR pathway.
Patients were divided into two cohorts based on HRR gene mutation status. Patients with mutations in either BRCA1, BRCA2 or ATM were randomized in Cohort A (245 patients: 162 Lynparza and 83 Investigator's Choice of NHA); 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 randomized in Cohort B (142 patients: 94 Lynparza and 48 Investigator's Choice of NHA). Patients with co-mutations (BRCA1, BRCA2 or ATM plus a Cohort B gene) were randomized in Cohort A. Patients were stratified by prior taxane use and evidence of measurable disease. All patients received a GnRH analog or had prior bilateral orchiectomy. Treatment was continued until disease progression. Patients randomized to the comparator arm were given the option to switch to Lynparza upon confirmed radiological BICR progression.
Patients with HRR gene mutations were identified based on prostate cancer tissue specimens that were tested centrally. HRR clinical trial assay was performed in a CLIA certified laboratory (CLIA HRR Clinical Trial Assay) or from reanalysis of data from a prior prostate cancer tissue test. (See Table 13.)
Click on icon to see table/diagram/imageDemographic and baseline patient characteristics in PROfound are summarized in Table 14. (See Table 14.)
Click on icon to see table/diagram/imageStudy Results: The study compared the efficacy of Lynparza (olaparib) treatment (300 mg [2x150 mg tablets] twice daily) with Investigator's Choice of prior NHA (enzalutamide or abiraterone acetate) in patients with HRR-mutated mCRPC.
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). TTPP is defined as at least a 2-point worsening from baseline of the pain score on Brief Pain Inventory-Short Form (BPI-SF) worst pain (Item 3) or an initiation of or an increase in opioid use.
An additional secondary end-point included in Cohort B was rPFS by BICR and additional secondary end-points included in both Cohort B and Cohort A+B, were 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 Lynparza 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 Lynparza arm vs comparator; and an improvement observed in confirmed radiological ORR in Cohort A+B. There was a statistically significant and clinical meaningful delay in TTPP in the Lynparza arm compared with the Investigator's Choice of NHA arm in Cohort A and the results in Cohort A+B were consistent with Cohort A.
The final analysis of OS (60% Maturity) demonstrated a statistically significant improvement in OS in patients randomized to Lynparza compared to patients in the Investigators Choice of NHA arm in Cohort A. In Cohort A, 56 out of 83 patients (67.5%) in the investigators choice of NHA arm received subsequent treatment with Lynparza. (See Table 15, Figures 16, 17 and 18.)
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Click on icon to see table/diagram/image
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Click on icon to see table/diagram/imageIn the PROfound trial, a PSA50 response was reported in 42.6% of Lynparza treated patients in Cohort A and in 30.5% of Lynparza treated patients in Cohort A+B.
In Cohort A the benefit of Lynparza over Investigator's Choice of NHA was maintained across all pre-defined subgroups. For Cohort A+B, the benefit of Lynparza over Investigator's Choice of NHA was maintained across the majority of pre-defined subgroups. Clinically meaningful reductions in the risk of radiological disease progression or death in Lynparza -treated patients ranged from 39% to 75% in Cohort A and from 23% to 88% in Cohort A+B.
The prevalence of the mutations in Cohort B did not provide sufficient power to test independently. The Cohort B exploratory analysis demonstrated a trend toward rPFS improvement (median rPFS of 4.8 months for Lynparza vs. 3.3 months for Investigator's Choice of NHA) and OS improvement (median OS of 14.1 months for Lynparza vs.11.5 months for Investigator's Choice of NHA at final analysis). ORR was [2/54 (3.7%) vs 2/24 (8.3%) Lynparza 300 mg bd vs NHA, respectively].
Treatment of BRCA-mutated Metastatic Castration-Resistant Prostate Cancer in Combination with Abiraterone and Prednisone or Prednisolone: PROpel: The efficacy of Lynparza in the treatment of patients with mCRPC was investigated in PROpel (NCT03732820), a randomized, double-blind, placebo-controlled, multi-center study that compared the efficacy of Lynparza in combination with abiraterone with placebo plus abiraterone for patients with mCRPC. Patients (n=796) were randomized (1:1) to receive Lynparza tablets 300 mg orally twice daily in combination with abiraterone 1000 mg daily (n=399) compared with placebo plus abiraterone (n=397). All patients received either prednisone or prednisolone 5 mg twice daily, and a GnRH analog or prior bilateral orchiectomy. Patients with prior treatment with abiraterone were excluded. Prior docetaxel for localized or metastatic hormone-sensitive prostate cancer (mHSPC) was allowed. Randomization was stratified by metastases (bone only, visceral, or other) and docetaxel treatment at mHSPC stage (yes or no). Lynparza treatment was continued until objective radiological disease progression determined by investigator or unacceptable toxicity.
BRCA gene mutation (BRCAm) status was assessed after randomization and before primary analysis by both NGS-based tumor tissue and ctDNA tests. BRCAm classification criteria in line with the FDA approved assays were used to determine the deleterious and suspected deleterious somatic or germline mutation status of patients.
The major efficacy outcome measure was investigator-assessed rPFS evaluated according to RECIST, version 1.1 and Prostate Cancer Working Group (PCWG3) (bone) criteria. Overall survival (OS) was an additional efficacy outcome measure.
Of the 796 patients tested, 85 (11%) had BRCAm determined by either a positive ctDNA test (9%) or a tumor tissue test (6%). Among these 85 patients, the median age was 68 years (range 43 to 85), and 67% were 65 years or older; 72% were White, 22% Asian, and 2% Black or African American; 66% had ECOG performance status (PS) 0 and 34% had ECOG PS 1; 25% had prior docetaxel treatment for mHSPC; 53% had bone-only metastases, 15% had visceral metastases, and 32% had other metastases.A statistically significant improvement in rPFS for Lynparza/abiraterone compared to placebo/abiraterone was observed in the intention to treat (ITT) population. In an exploratory analysis in the subgroup of 711 patients without an identified BRCAm, the rPFS hazard ratio was 0.77 (95% CI: 0.63, 0.96) and the OS hazard ratio was 0.92 (95% CI: 0.74, 1.14), indicating that the improvement in the ITT population was primarily attributed to the results seen in the subgroup of patients with BRCAm.
Results of an exploratory analysis in the subgroup of 85 patients on PROpel with BRCAm are summarized in Table 16 and Figure 19.
Results from the BICR assessment were consistent with the investigator-assessed rPFS results. (See Table 16, Figure 19 and Figure 20.)
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Click on icon to see table/diagram/imagePharmacokinetics: 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 UGT1A4, UGT1A9, 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: 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.
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.
Carcinogenicity: Carcinogenicity studies have not been conducted with olaparib.
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.
