Studies of PARP Inhibitors for Ovarian Cancer
The first evidence of PARP inhibition and synthetic lethality in patients with different types of refractory solid tumors was established in a phase I trial that included a pharmacokinetic and pharmacodynamic analysis of olaparib. Selection of patients sought to include a BRCA mutation carriers enriched population. Sixty patients were enrolled and 22 were carriers of a BRCA mutation. Olaparib was well tolerated and antitumor activity was reported in mutation carriers with ovarian, breast or prostate cancer. To further evaluate this activity, this study was expanded to evaluate olaparib in a cohort of BRCA mutation carriers with advanced ovarian cancer and differing platinum-free intervals. Fifty patients were treated, 13 had platinum-sensitive recurrent disease, 24 had platinum-resistant disease and 13 had platinum-refractory disease. Platinum-free interval was found to be associated with response to olaparib, but antitumor activity in platinum-refractory and resistant disease was also observed.
Given the promising results of olaparib in the previous studies, there was great interest in defining the best way to incorporate it into clinical practice. A phase II, multicenter, open-label, randomized study of ovarian cancer patients that recurred within 12 months of completion of platinum therapy and had a BRCA germline mutation, was carried out. The study evaluated twice-daily continuous olaparib at doses of 200 or 400 mg versus pegylated liposomal doxorubicin 50 mg/m2 intravenously every 4 weeks. Ninety-seven patients were assigned to the treatment groups. No difference was observed in the end points of PFS or overall response rate (ORR), but the ORR for olaparib 400 mg (31%) was consistent with previous reports. A possible imbalance between olaparib and PLD arms may have led to an underestimation of olaparib benefit.
Olaparib treatment was first approved in the United States under the provisions of accelerated approval in 2014. The decision was based on another phase II, multicenter study that evaluated the efficacy and safety of olaparib in a spectrum of BRCA mutation associated tumors, including 193 patients with heavily pretreated ovarian cancer, 148 (77%) of those with a germline mutation in BRCA gene. All patients were considered to be platinum-resistant or not candidates to receive platinum-based therapy. In the ovarian cancer cohort, the tumor response rate was 31.1%, median PFS was 7 months and median OS was 16.6 months. Responses to olaparib were observed across different cancer types, supporting the hypothesis that therapy directed against BRCA deficient cells has activity regardless of anatomic organ of origin. Afterwards, the efficacy and safety of olaparib was confirmed in a subgroup of patients with germline BRCA mutated ovarian cancer who had received at least 3 prior lines of chemotherapy (Table 1). The FDA approval of olaparib as monotherapy is in germline BRCA mutated advanced ovarian cancer after having received 3 or more lines of prior chemotherapy. After these results, the SOLO3 trial was designed as a phase III confirmatory trial to demonstrate a positive result versus chemotherapy in advanced ovarian cancer.
To further evaluate the efficacy and safety of olaparib in women with recurrent ovarian cancer and a documented germline BRCA mutation, a pooled analysis of two phase I and four phase II trials, including the previously cited trials, was published. Of the 300 patients, 205 (75%) had received ≥3 lines of prior chemotherapy. Treatment with olaparib was associated with an ORR of 36% and a median duration of response of 7.4 months. Treatment with olaparib had an acceptable and manageable safety profile and most important adverse events were tolerable nausea and fatigue.
The second olaparib FDA approval as a maintenance therapy for recurrent, platinum-sensitive disease was based on the results of Study 19, a phase II, double-blind, placebo-controlled, randomized trial enrolling 265 patients who were clinically enriched for PARP inhibitor treatment response markers (i.e., women with relapsed, platinum-sensitive, high-grade serous ovarian cancer) and showed a response to their most recent platinum-based chemotherapy (Table 2). Patients were assigned to receive olaparib capsules, at a dose of 400 mg twice daily or placebo. After 153 events, the analysis showed that PFS was 3.6 months longer in the olaparib group (from 4.8 to 8.4 months) and the toxicity profile was manageable. A pre-planned, retrospective analysis demonstrated that BRCA mutated patients obtained the greatest benefit from the PARP inhibitor (HR 0.18, P<0.0001), however, an advantage was also seen for BRCA wild type treated patients (HR 0.54, P<0.0075). Long term efficacy and safety analysis showed an apparent OS advantage irrespective of BRCA mutation and a low incidence of discontinuations due to adverse events (6%).
The efficacy of maintenance treatment with olaparib in platinum-sensitive recurrent ovarian cancer was confirmed in the SOLO2 trial, a phase III, double-blind, placebo-controlled trial of 295 patients with germline BRCA mutated ovarian cancer that had received ≥2 prior platinum-based chemotherapy regimens and had a complete or partial response. Patients were randomized to either a new tablet formulation of olaparib (two 150 mg tablets taken orally, twice daily) or placebo until progression. The hazard ratio for PFS was 0.30 (P<0.0001), corresponding to a 13.6-month improvement (from 5.5 to 19.1 months). Olaparib maintenance was also related to a significant improvement in time to second progression, time to first, and time to second subsequent therapies. The most common grade 1–2 events reported in ≥20% in patients that received olaparib were nausea (73%), fatigue or asthenia (62%), vomiting (35%), diarrhea (32%) dysgeusia (27%), headache (25%), anemia (24%), abdominal pain (22%), hyporexia (22%) and constipation (21%). Grade 1–2 neutropenia and thrombocytopenia occurred in 14% and 13% of patients. The incidence of grade 3–4 events was low. The only grade 3–4 event with an incidence of ≥10% was anemia (19%). Furthermore, health-related quality of life was not affected while on treatment. The new tablet formulation reduces the treatment burden from 16 capsules to four tables per day.
The SOLO1 trial was conducted to evaluate the efficacy of maintenance treatment with olaparib tablets in women with newly diagnosed stage III or IV ovarian cancer, with a mutation in BRCA, and that obtained a response after first line platinum-based chemotherapy. The SOLO1 randomized, double-blind, placebo-controlled trial was conducted in 391 ovarian cancer patients. The use of maintenance olaparib provided a substantial PFS benefit, with a 70% lower risk of progression (HR 0.30; P<0.001), corresponding to a median PFS of 13.8 months in the placebo arm and a not reached median with olaparib after nearly 3 years of follow-up. Significant increases in time to first subsequent therapy and time to second disease progression were also noted with olaparib. Although most patients in this trial had a germline BRCA mutation, the results with other PARP inhibitors suggest that the findings could be expanded to patients with a somatic BRCA mutation. This led to the FDA approval for the maintenance treatment of patients with deleterious or suspected deleterious germline or somatic BRCA mutated advanced ovarian cancer who obtained a response (complete or partial) after platinum-based chemotherapy.
The SOLO3 study was presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting. This study randomly assigned 178 patients with platinum-sensitive, BRCA mutated recurrent ovarian cancer in order to confirm a benefit from treatment with olaparib monotherapy compared with physician's choice chemotherapy treatment. ORR for olaparib by blinded independent review was 72% in contrast with 51% in the chemotherapy arm (OR 2.53; P=0.002). In addition, olaparib derived a 38% progression risk decline compared with chemotherapy (HR, 0.62) and a median PFS benefit of 4.2 months (13.4 vs. 9.2 months; P=0.13). In accordance with these results, chemotherapy-free treatment may be a reasonable treatment option for women with BRCA mutation and platinum-sensitive relapsed ovarian cancer.
Niraparib is a PARP inhibitor that demonstrated inhibition of tumor growth in preclinical models with loss of BRCA function. A two-part, phase I dose-escalation study of niraparib was undertaken in human carriers of BRCA mutations and ovarian and prostate cancers, in order to assess pharmacokinetic and pharmacodynamic profiles, as well as antitumor activity. Patients were not suitable to receive any established treatment. A total of 100 patients were enrolled and 49 had ovarian cancer. The maximum tolerated dose was 300 mg/day. Antitumor activity was achieved in both mutated and wild type BRCA patients. Responses were documented in 8 of 20 (40%) BRCA mutated ovarian cancer patients. Out of 3 patients with wild-type BRCA, platinum-sensitive ovarian cancer, 2 (67%) achieved durable partial responses by RECIST or CA 125 or both. The use of niraparib was associated with a low frequency of serious adverse events.
The NOVA study was a phase III, randomized, double-blind trial that sought to evaluate the efficacy and safety of niraparib (300 mg orally daily) as maintenance treatment for patients with platinum-sensitive, relapsed ovarian cancer. Patients were eligible regardless of germline BRCA mutation status and were categorized in a germline-mutated (gBRCA) and a non-germline mutated (non-gBRCA) cohort. Before the database lock, tissue samples were tested to identify the population of patients in the non-gBRCA cohort in whom tumors had homologous recombination deficiency (HRD-positive subgroup). A total of 553 patients were enrolled, 201 in the gBRCA and 345 in the non-gBRCA cohort. In the gBRCA cohort, the median PFS was 21 months in the niraparib group and 5.5 months in the placebo group (HR, 0.72; P<0.001). A PFS benefit of niraparib was also documented in the non-gBRCA cohort (median, 9.3 vs. 3.9 months; HR, 0.45; P<0.001) and in the HRD-positive subgroup (median, 12.9 vs. 3.8 months; HR, 0.38; P<0.001). Bone marrow toxicity was moderate and manageable. The incidence of grade 1–2 thrombocytopenia, anemia and neutropenia in patients with niraparib was 28%, 25% and 11%, respectively. Common non-hematologic grade 1–2 toxicities were nausea (71%), fatigue (51%), constipation (39%), vomiting (32%), headache (26%), hyporexia (25%), insomnia (24%) and abdominal pain (22%). Grade 3–4 toxicity was mainly represented by thrombocytopenia (34%), anemia (25%) and neutropenia (20%). Quality of life does not appear to be affected by use of niraparib. FDA first approval of niraparib in 2017 was based upon these results and assigned for the maintenance treatment of patients with recurrent ovarian cancer who are in a complete or partial response to platinum-based chemotherapy. Niraparib was the first PARP inhibitor to be approved that does not require BRCA mutation.
The indication of niraparib as monotherapy is based on data from the QUADRA study, a phase II, multi-center, open label, single arm clinical trial that evaluated its activity and safety in ovarian cancer patients who had been treated with three or more previous chemotherapy regimens. The primary objective was the ORR in the primary efficacy population (e.g., patients with HR-deficient tumors sensitive to their last platinum-based therapy who had received 3–4 previous regimens). Of a total of 463 patients, 47 were included in the primary efficacy population and gained an ORR of 28% (P=0.00053). This led to approval from the FDA for the treatment of advanced ovarian cancer patients who have been treated with three more prior chemotherapy regimens and have an HR-deficiency positive status by either a deleterious or suspected deleterious BRCA mutation or genomic instability, and who have progressed more than 6 months after response to the last platinum-based chemotherapy. This represents the first time a PARP inhibitor has been approved as monotherapy for women with ovarian cancer, regardless or their BRCA mutation status, in the heavily pretreated setting.
To test the activity and safety of niraparib maintenance after frontline treatment, the PRIMA trial was designed and carried out. This phase III, randomized, double-blind trial assigned patients (N=733) with newly diagnosed advanced ovarian cancer to receive niraparib maintenance therapy or placebo after a response to platinum-based chemotherapy. Tumor samples were tested to identify those with HR-deficiency, determined as the presence of a BRCA mutation, a score of ≥42 on the myChoice test, or both. In patients with HR-deficiency the median PFS was 21.9 months with niraparib and 10.4 without niraparib (HR, 0.43; P<0.001). Median PFS in the overall population was 13.8 months with niraparib and 8.2 months with placebo (HR, 0.62; P<0.001). These results confirmed that benefit of niraparib is present regardless of the presence or absence of HR-deficiency.
The effect of rucaparib in humans was first assessed in combination with temozolomide in a phase I trial of patients with different solid tumors. In this study, patients received intravenous escalating doses of rucaparib in combination with temozolomide (100 mg/m2/d for 5 days every 28 days) to establish the PARP inhibitory dose. The PARP inhibitory dose was 12 mg/m2 on the basis of a 74% to 97% inhibition of peripheral blood lymphocytes PARP activity.
A phase II study investigated different schedules and dose levels of rucaparib in patients with germline BRCA mutant breast or ovarian cancers. This study provided evidence that continuous dosing of oral rucaparib is required for optimal response and derives a greater benefit than intermittent intravenous dosing. After these observations, recruitment to the intravenous formulation cohorts was discontinued. However, the maximum oral dose of rucaparib was not sufficiently evaluated.
Study 10 was a three-part, phase I–II trial to evaluate efficacy, toxicity, and the recommended phase II dose based on the maximum tolerate dose. Part 1 (phase I of dose escalation) included 56 women with breast or ovarian cancer with or without a BRCA mutation. No maximum tolerated dose was identified and the 600 mg twice-daily was selected as a recommended phase II dose. Part 2A (phase II expansion) assessed the efficacy of rucaparib in women with platinum-sensitive recurrent ovarian cancer with a germline BRCA mutation. Of 42 patients, 25 (59.6%) achieved a RECIST response. Rucaparib showed a manageable safety profile.
The ARIEL2 trial was a two-part, single arm, phase II trial designed to assess efficacy and safety of rucaparib. In part 1, participants (N=204) had ovarian cancer and at least one previous platinum therapy. They were classified into one of three predefined HR-deficiency subgroups: BRCA mutant (germline or somatic), BRCA wild-type and loss of heterozygosity (LOH) high, and BRCA wild-type and LOH low. Median PFS was 12.8, 5.7 and 5.2 months for BRCA mutant, BRCA wild-type and LOH high, and BRCA wild-type and LOH low subgroups. These outcomes suggest that assessment of LOH status can be used as a reliable biomarker. Part 2 is an extension that includes ovarian tumors that are platinum-sensitive, platinum-resistant, or platinum-refractory and received 3–4 prior chemotherapies. Results from ARIEL2 part 2 are still pending.
The efficacy of oral rucaparib at a dose of 600 mg twice daily was also evaluated in a combined analysis of patients from Study 10 (part 2A) and ARIEL2 (parts 1 and 2) who had ovarian cancer, received ≥2 prior lines of chemotherapy and had a deleterious germline or somatic BRCA mutation (N=106). This population obtained an ORR of 53.8%, a 34% rate of stable disease and a manageable safety profile. The results of the pooled analysis of these two phase II trials (Study 10 and ARIEL2) led to the accelerated FDA approval of rucaparib for the treatment of patients with ovarian cancer associated with a deleterious germline or somatic BRCA mutation who have received ≥2 lines of chemotherapy.
Rucaparib has also proved effective as a maintenance treatment option for platinum-sensitive relapsed ovarian cancer. The ARIEL3 study was a phase III, randomized, double-blind, placebo controlled trial including 564 patients with ovarian cancer who had received at least two previous platinum-based chemotherapy regimens and achieved a response to their last platinum-based regimen. The BRCA mutation status and the size of residual disease were not restricted. Patients were assigned to a rucaparib 600 mg twice daily arm or a placebo arm. They were categorized into three cohorts: patients with germline or somatic BRCA mutations, patients with HR-deficiencies (high loss of heterozygosity), and the intention-to-treat population. Median PFS in BRCA mutation carriers was 16.6 months in the rucaparib group and 5.4 months in the placebo group (HR, 0.23; P<0.0001). In patients with an HR-deficiency it was 13.6 and 5.4 months (HR, 0.32; P<0.0001). In the intention-to-treat population, it was 10.8 and 5.4 months (HR, 0.36; P<0.0001). Grade 1–2 hematologic toxicities included thrombocytopenia (23%), anemia (19%) and neutropenia (18%). Common non-hematologic grade 1–2 toxicities that occurred across ≥20% of patients that received rucaparib were nausea (72%), fatigue (asthenia) (63%), dysgeusia (39%), constipation (35%), vomiting (33%), diarrhea (31%), abdominal pain (27%) and hyporexia (23%) and increase in aminotransferase concentrations (23%). The most common treatment-emergent adverse events of grade 3–4 were anemia (19%) and increase in aminotransferase concentrations (10%).
Chin Clin Oncol. 2020;9(4):51 © 2020 AME Publishing Company