ABSTRACT & COMMENTARY
More Promise from Olaparib in Recurrent Ovarian Cancer: The BRCA Cohort
By Robert L. Coleman, MD
Professor, University of Texas; M.D. Anderson Cancer Center, Houston
Dr. Coleman reports he receives research funding from Clovis Pharmaceuticals, who is developing rucaparib, a PARP inhibitor in women with ovarian cancer, and serves as co-principle investigator for several AztraZeneca sponsored trials of olaparib and other agents.
Olaparib, a poly (ADP)-ribose polymerase (PARP) inhibitor, demonstrated substantial delay until progression when administered to women as a maintenance therapy with BRCA-mutant recurrent ovarian cancer.
Ledermann J, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: A preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 2014;15:852-861.
In a previous report, maintenance monotherapy with olaparib significantly prolonged progression-free survival (PFS) vs placebo in patients with platinum-sensitive recurrent serous ovarian cancer. The current analysis explores the hypothesis that olaparib is most likely to benefit patients with a BRCA mutation. A retrospective, preplanned analysis of data by BRCA mutation status from the original randomized, double-blind, Phase 2 study was conducted. Olaparib was administered at 400 mg twice daily and was compared to placebo in patients with platinum-sensitive recurrent serous ovarian cancer who had received two or more platinum-based regimens and who had attained at least a partial response to their most recent platinum-based regimen. Randomization was stratified by time to progression on penultimate platinum-based regimen, response to the most recent platinum-based regimen before randomization, and ethnic descent. The primary endpoint was PFS, analyzed for the overall population and by BRCA status. Two hundred sixty-five patients were randomized: 131 of 136 patients (96%) randomized to olaparib had their BRCA status known, of which 74 (56%) carried deleterious mutations. Similarly, 123 of 129 (95%) placebo patients had BRCA status known, of whom 62 (50%) were deleterious. Of patients with a BRCA mutation, median PFS was significantly longer in the olaparib group than in the placebo group (11.2 months vs 4.3 months; hazard ratio [HR], 0.18; 95% confidence interval [CI], 0.10-0.31; P < 0.0001); similar findings were noted for patients with wild-type BRCA, although the difference between groups was lower (7.4 months vs 5.5 months; HR, 0.54; 95% CI, 0.34-0.85; P = 0.0075). At the second interim analysis of overall survival (58% maturity), overall survival did not significantly differ between the randomized cohorts (HR, 0.88; 95% CI, 0.64-1.21; P = 0.44), the patients with mutated BRCA (HR, 0.73; 95% CI, 0.45-1.17; P = 0.19), and the patients with wild-type BRCA (HR, 0.99; 95% CI, 0.63-1.55; P = 0.96). Serious adverse events were reported in 25 (18%) patients who received olaparib and 11 (9%) who received placebo. The most common grade 3 or worse adverse events in the olaparib group were fatigue (7% vs 3%) and anemia (5% vs < 1%). Tolerability was similar in patients with mutated BRCA and the overall population. These results support the hypothesis that patients with platinum-sensitive recurrent serous ovarian cancer with a BRCA mutation have the greatest likelihood of benefiting from olaparib treatment.
COMMENTARY
Recurrent ovarian cancer, for the most part, is incurable with currently available treatment strategies. And while several promising new therapies are under active investigation, it is generally agreed that they are unlikely to be associated with a robust and lasting treatment effect due to the heterogeneity of ovarian cancer biology and the therapeutic target of interest. This concern drives the impetus to clearly define the roles of selected tumor targets and the effort to develop companion diagnostics that could accurately identify patients most likely to benefit from a specific therapy. Ovarian cancer is a disease characterized by global genomic instability and few driving mutations.1 However, our understanding of DNA repair mechanisms has identified a limited number of genes, such as BRCA, that could be leveraged for therapy.2-5
The current study was a large, placebo-controlled, double-blind, randomized, Phase 2 study of the PARP inhibitor olaparib in women with recurrent platinum-sensitive ovarian cancer. In the initial analysis, olaparib was associated with a significant, near doubling of PFS compared to placebo.6 At the time of the initial report, limited data on BRCA mutation status were known. The current report provides this information on 95% of the study subjects. The study was clearly enriched for these patients with more than 50% being BRCA-positive. This is neither an uncommon finding among platinum-sensitive patients nor in trials of PARP inhibitors because the potential benefit of this class of agent is well known. Unique in this trial, though, was expansion of the BRCA analysis to somatic (tumor) BRCA mutation, which contributed another 15% to the BRCA germline population. Taken together, the impact of using a drug that has synthetic lethality under mutant BRCA conditions was substantial — and clinically meaningful — accounting for a near 7-month delay in progression. The authors tried to provide some context to this endpoint by measuring the times to both the next line of therapy and the subsequent line of therapy following this. In both instances, the effect was maintained. Overall survival, now nearly 60% mature, was still no different between the arms; however, crossover treatment to a subsequent PARP inhibitor in the placebo arm was 23% (vs 0%), which could confound this endpoint.
The sponsor of this trial (AstraZeneca) recently presented these data to the U.S. FDA’s Oncologic Drug Advisory Committee (ODAC) for accelerated approval (June 25, 2014, www.fda.org/ODAC). Several concerns were raised by the committee about the retrospective subgroup analyses, particularly in the assessment of toxicity, lack of patient reported outcomes, and a seemingly under performance of the control group. While extremely rare, myelodysplastic syndrome was diagnosed in three patients (vs one patient) in the olaparib arm, and while severe gastrointestinal toxicity and treatment discontinuations were uncommon findings (4.4% vs 1.6%, P = NS), the impact of low level (Grade 1-2) gastrointestinal toxicity to an otherwise asymptomatic population is not trivial and was not captured well in the study. Finally, the expected PFS in the statistical plan was 9 months in the placebo arm, but was just 4.8 months in the trial, raising questions about a spurious positive result. Nevertheless, despite the committee’s unfavorable vote (2 for, 11 against), the data strongly support the hypothesis that administering a drug in this class to patients whose tumors are vulnerable due to BRCA loss would have clinically meaningful treatment effects. Fortunately, there are multiple confirmatory Phase 3 trials underway with several PARP inhibitors. Hopefully, these will confirm these observations and encumber the first truly individualized cancer therapeutic for women with ovarian cancer.
References
- Cancer Genome Atlas Research N, Kandoth C, et al. Integrated genomic characterization of endometrial carcinoma. Nature 2013;497:67-73.
- Murai J, et al. Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res 2012;72:5588-5599.
- Hutchinson L. Targeted therapies: PARP inhibitor olaparib is safe and effective in patients with BRCA1 and BRCA2 mutations. Nat Rev Clin Oncol 2010;7:549.
- Penning TD. Small-molecule PARP modulators Current status and future therapeutic potential. Curr Opin Drug Discov Devel 2010;13:577-586.
- Carden CP, et al. PARP inhibition: Targeting the Achilles’ heel of DNA repair to treat germline and sporadic ovarian cancers. Curr Opin Oncol 2010;22:473-480.
- Ledermann J, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med 2012;366:1382-1392.
