FDA Panel Votes Proposed Olaparib/Abiraterone Indication Should Be Restricted to BRCA-Mutant mCRPC

In an 11-to-1 vote, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted the indication of the PARP inhibitor olaparib (Lynparza) in combination with abiraterone acetate (Zytiga) and prednisone or prednisolone for the initial treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) should be restricted to patients whose tumors harbor a BRCA mutation.¹

One voter abstained from the vote, indicating that the voter felt the combination should not be approved for any indication.

“I voted yes [to restrict the indication],” said Christopher Lieu, MD, co-director, GI Medical Oncology Program and associate director for clinical research, at the University of Colorado Cancer Center in Aurora. “The question here is, ‘Does [the phase 3 PROpel trial (NCT03732820)] prove that patients with non-BRCA–mutated prostate cancer benefit from olaparib?’ And I believe that the answer is, ‘We don’t know.’ There is a concern about the entire class of PARP inhibitors in an unselected population and we see that in other diseases. This is only further supported by the negative results in the BRCA-negative population in the only prespecified study conducted thus far in prostate cancer, the [phase 3] MAGNITUDE study [NCT03748641].”

In August 2022, the FDA granted priority review to a supplemental new drug application (sNDA) for olaparib plus abiraterone and prednisone or prednisolone for the treatment of adult patients with mCRPC.² Olaparib was previously granted regular approval by the FDA in May 2020 for the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated mCRPC, who have progressed following prior treatment with enzalutamide or abiraterone.³

ODAC primarily considered findings from the PROpel trial to make their decision. PROpel randomly assigned patients 1:1 to receive either abiraterone plus prednisone or prednisolone in combination with olaparib (n = 399) or placebo (n = 397). The primary end point of the study was radiographic progression-free survival (rPFS) by investigator assessment. Overall survival (OS) represented a key secondary end point, with other secondary outcome measures including time to first subsequent therapy or death, time to second progression or death (PFS2), and health-related quality of life.⁴

According to data from the primary analysis of PROpel, patients experienced a median rPFS by investigator assessment of 24.8 months vs 16.6 months in the olaparib and placebo arms, respectively (HR, 0.66; 95% CI, 0.54-0.81; P < .001). In an exploratory subgroup analysis, investigators noted that patients with HRR-mutant disease (HR, 0.50; 95% CI, 0.34-0.73) and non-HRR–mutant disease (HR, 0.76; 95% CI, 0.60-0.97) experienced a benefit in terms of investigator-assessed rPFS.⁴

HRR status was determined by tumor tissue testing, circulating tumor DNA (ctDNA) testing, and aggregated tumor tissue and ctDNA test results. The aggregate HRR-mutant population (n = 226) consisted of 90 patients positive by tumor tissue and ctDNA, 28 positive by tumor tissue, and 108 positive by ctDNA. The non-HRR–mutant population (n = 552) included 328 negative by tumor tissue and ctDNA, 38 negative by tumor tissue, and 186 negative by ctDNA.⁴

Regarding safety, the adverse effect (AE) profile of abiraterone and olaparib was consistent with the known toxicity profiles of the individual agents, and findings did not suggest the combination increased the toxicity of either agent. Patients experienced any-grade AEs at a rate of 97.2% in the olaparib arm compared with 94.9% in the placebo arm. Grade 3 or higher AEs were present in 47.2% and 38.4% of patients, respectively. Common any grade AEs in the investigational arm included anemia (46.0%), fatigue or asthenia (37.2%), and nausea (28.1%).⁴

Findings from the final OS analysis of PROpel, which were presented during the 2023 Genitourinary Cancers Symposium, showed that the median OS achieved in the olaparib arm was 42.1 months vs 34.7 months in the placebo arm (HR, 0.81; 95% CI, 0.67-1.00; P = .0544). The OS data were at 47.9% maturity at the time of the October 12, 2022, cutoff. Study authors noted that this was the longest median OS reported to date in a phase 3 trial in first-line mCRPC.⁵

Within this analysis, investigators also presented results for patients in BRCA-mutant (n = 85) and non-BRCA–mutant (n = 693) subgroups, as determined by the same aggregate method used to prospectively determine HRR status. The median OS in the BRCA-mutant subgroup was not reached in the olaparib arm compared with 23.0 months in the placebo arm (HR, 0.29; 95% CI, 0.14-0.56). Notably, the benefit observed with the addition of olaparib was much less pronounced in the non-BRCA–mutant subgroup, with a median OS of 39.6 months vs 38.0 months for the olaparib and placebo arms, respectively (HR, 0.91; 95% CI, 0.73-1.13).⁵

ODAC also briefly reviewed findings from the phase 2 study 8 (NCT01972217), which was a small exploratory trial with a similar design to PROpel that served as a proof-of-concept study. The study randomly assigned patients with mCRPC who were previously treated with docetaxel to receive either abiraterone plus olaparib (n = 71) or abiraterone plus placebo (n = 71). The trial was double blinded with no patient stratification, and the primary end point was rPFS per investigator assessment.⁶

Topline results from study 8 showed that, at the September 22, 2017, data cutoff, patients who received the combination achieved a median rPFS of 13.8 months (95% CI 10.8-20.4) compared with 8.2 months (95% CI, 5.5-9.7) among those in the placebo arm (HR, 0.65; 95% CI, 0.44-0.97; P = .034). Additionally, the addition of olaparib offered a slight benefit in terms of OS (HR, 0.91; 95% CI, 0.60-1.38).^1,6

Despite the positive findings from these 2 trials, ODAC noted that, in the committee's opinion, the trial design of PROpel was inadequate due to the enrollment of a heterogeneous population that was unstratified by BRCA mutation status, an insufficient determination of BRCA mutation status, and the potential for harm caused by the addition of olaparib in non-BRCA–mutant subgroups.¹

“PROpel enrolled an intent-to-treat population that included all patients, regardless of BRCA or HRR mutation status, unstratified by mutation status with no alpha-controlled analysis plan for these subgroups,” Chana Weinstock, MD, the acting supervisory associate director of Division of Oncology, Office of Oncologic Diseases at the FDA, said in the introductory comments. “We would consider this trial design inappropriate today. Given emerging data on the strength of BRCA mutations as predictive biomarkers for PARP inhibitors, BRCA [mutation] status should have been prospectively evaluated, with efficacy results analyzed separately for biomarker-selected subgroups. This is a significant design flaw that other sponsors designing similar studies have more appropriately addressed, and we would be rewarding poor trial design if we disregarded this issue.”

In their rebuttal, the sponsors of PROpel argued that findings from study 8 demonstrated a clinical benefit with abiraterone plus olaparib irrespective of biomarker status, leading to the design of PROpel in an all-comer mCRPC population. They noted that in May 2018, a type B meeting was held with the FDA to discuss key study design elements, including patient population, primary and secondary end points, and eligibility criteria. The sponsors also said that the design of the trial was partially due to the mechanism of action of the combination, where the greatest effect will be seen in BRCA-mutant patients, but patients without BRCA or HRR mutations would still experience anticancer activity.

Later in their presentation, investigators explained that they did not stratify for HRR or BRCA mutations in PROpel because study 8 did not demonstrate these mutations to be predictive of benefit with the combination, there was limited evidence in 2018 that these mutations were prognostic factors, and stratification did occur with known prognostic factors. However, they contended that PROpel provides reliable estimates of treatment effect in biomarker subgroups, as patients in the BRCA-mutant and non-BRCA–mutant subgroups were well balanced between the arms of the trial, and the baseline characteristics within the non-BRCA–mutant group were also well balanced.

There was some contention as to how BRCA status was determined, with ODAC only considering patients with both ctDNA and tumor tissue findings (n = 427) to be truly non-BRCA–mutant, with the other 284 patients falling into an undetermined BRCA mutation classification. They argued that a small number of these undetermined patients could have an undetected BRCA mutation, adding uncertainty and opening the door for the inclusion of patients who are truly BRCA-mutant negative who would be exposed to harms caused by add-on therapy. In their further breakdown, ODAC determined that the OS hazard ratio in the undetermined group was 0.73 in favor of olaparib, but in the true non-BRCA–mutant patients the OS HR was 1.06.¹

“The applicants provided clear benefit of olaparib plus abiraterone in patients with the BRCA mutation,” Ashley Rosko, MD, medical directorof the oncogeriatric program and an associate professor of medicine at The Ohio State University Comprehensive Cancer Center in Columbus, said. “[However], the majority of patients will not carry this mutation. Many of the team that are here on the call, and the applicant as well, indicated this heterogeneity in the disease pathogenesis, and I believe an all-comers indication argues against personalizing therapy for mCRPC. I support restriction [of the indication] to patients with a BRCA mutation.”

References

1. Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA. April 28, 2023. Accessed April 28, 2023. https://www.youtube.com/live/KPyIswlHGPM
2. FDA accepts submission of supplemental new drug application for LYNPARZA® (olaparib) in combination with abiraterone and prednisone or prednisolone for patients with metastatic castration-resistant prostate cancer and grants priority review. News release. August 16, 2022. Accessed April 28, 2023. https://www.merck.com/news/fda-accepts-submission-of-supplemental-new-drug-application-for-lynparza-olaparib-in-combination-with-abiraterone-and-prednisone-or-prednisolone-for-patients-with-metastatic-castration-resista/
3. FDA approves olaparib for HRR gene-mutated metastatic castration-resistant prostate cancer. News release. May 19, 2020. Accessed April 28, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olaparib-hrr-gene-mutated-metastatic-castration-resistant-prostate-cancer
4. Clarke NW, Armstrong AJ, Thiery-Vuillemin A, et al. Abiraterone and olaparib for metastatic castration-resistant prostate cancer. NEJM Evid. 2022;1(9). doi:10.1056/EVIDoa2200043
5. Clarke NW, Armstrong AJ, Thiery-Vuillemin A, et al. Final overall survival (OS) in PROpel: Abiraterone (abi) and olaparib (ola) versus abiraterone and placebo (pbo) as first-line (1L) therapy for metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2023;41(suppl 6):LBA16. doi:10.1200/JCO.2023.41.6_suppl.LBA16
6. Clarke N, Wiechno P, Alekseev B, et al. Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2018;19(7):975-986. doi:10.1016/S1470-2045(18)30365-6