FDA's ODAC Votes Yes to Olaparib Combination Being Restricted to BRCAm mCRPC


The Oncologic Drugs Advisory Committee has discussed the approval application for olaparib plus abiraterone and prednisone or prednisolone for patients with metastatic castration-resistant prostate cancer and voted on its potential future.

The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 11 to 1 in favor of restricting the supplemental new drug application (sNDA) for olaparib (Lynparza) in combination with abiraterone (Zytiga) and prednisone or prednisolone for treatment of adult patients with metastatic castration-resistant prostate cancer (mCRPC) to patients with BRCA-mutant (BRCAm) tumors only. One member obstained from voting.1

The decision of the ODAC was based on a discussion of the study’s pre-specified analyses. The sNDA seeks approval for the general population of adult patients mCRPC, but supporting evidence did not include a subgroup analysis of patients with BRCAm. In addition, the FDA is concerned about the study not being alpha-controlled.

Evidence supporting the sNDA for the olaparib combination comes from the phase 3 PROpel study (NCT03732820), in which the combination achieved a 34% reduction in the risk of disease progression or death in patients with mCRPC compared with abiraterone alone (HR, 0.66; 95% CI, 0.54-0.81; P <.0001). The median radiographic progression-free survival (rPFS) achieved with olaparib in combination with abiraterone and prednisone or prednisolone was 24.8 months vs 16.6 months with abiraterone alone.2

The combination was safe and tolerable, and all toxicities were consistent with the known profiles of each drug individually. Anemia was the most common grade ≥ 3 adverse event (AE) reported in the study and occurred in 15.1% vs 3.3% of patients.

The results are from a group of 796 adult patients with mCRPC who were receiving androgen deprivation with gonadotropin-releasing hormone analogue or bilateral orchiectomy, were candidates for abiraterone therapy, had documented evidence of progressive disease, adequate organ function, and an ECOG performance score of 0 or 1. Patients were administered olaparib 300 mg in 2 tablets of 150 mg each, twice a day, and abiraterone was given in 1000 mg doses once per day. The primary end point of the PROpel study was rPFS and the secondary end points included overall survival (OS), time to first subsequent anticancer therapy or death, time to pain progression, and number of AEs.

Despite the positive findings of the study, the FDA asked the ODAC to discuss the sNDA and vote on whether the proposed indication for the combination of olaparib with abiraterone and prednisone or prednisolone should be restricted to the adult patients with mCRPC whose tumors are positive for a BRCAm.1

FDA’s Viewpoint

Based on the mechanism of action of PARP inhibitors like olaparib, tumors with mutations in the homologous recombination repair (HRR) pathway have been shown to respond well to PARP inhibition, according to Chana Weinstock, MD, who spoke on behalf of the FDA. These mutations include BRCA1, BRCA2, ATM, CHEK2, CDK12, and others. Therefore, patients without a BRCAm tumor may not have the same outcomes.

“We've seen with longer follow-up of maintenance use of PARP inhibitors in ovarian cancer that potential overall survival detriments and mutation negative patients have emerged, leading to recent restriction of previously broad approvals to BRCA mutation populations only. We’ve also seen the MAGNITUDE trial [NCT03748641] of a PARP inhibitor and prostate cancer, which pre-screened and stratified by HRR and BRCA mutation status, allowing better determination of efficacy and safety, and then now, the unmutated population of the non-HRR cohort was stopped early for futility, "said Weinstock, supervisory associate director (acting), Division of Oncology 1, Office of Oncologic Diseases, FDA, during the presentation.

Although there was a statistically significant rPFS benefit in the intent-to-treat (ITT) population of PROpel, Weinstock explained that this could be the result of substantial benefit in the BRCAm subgroup, but no subgroup analysis data are available to confirm or deny this. Additionally, there could be OS detriments among patients who are negative for a BRCAm, as well as in the non-BRCAm population. Weinstock also stated that patients with non-BRCAm mCRPC may experience prolonged exposure to the toxicities of olaparib.

“There's precedent for limiting use of a drug based on post hoc analysis and a subgroup with possible compromised safety or overall survival detriment, including such examples as mutation in colon cancer and squamous histology and non–small cell lung cancer. FDA guidance specifically states that if a trial demonstrates benefit only in patients in a selected subgroup, FDA may limit the indication to a narrower population than the original broad population enrolled overall,” Weinstock stated.

Applicant’s Stance

AstraZeneca, sponsor of the PROpel study, brought several experts to the ODAC meeting to discuss the benefit/risk profile of olaparib when combined with abiraterone and prednisone or prednisolone and responded to the concerns raised by the FDA. Neal Shore, MD, provided commentary from the perspective of a community oncologist and addressed why the sNDA for the olaparib combination is compelling.

Hormonal therapies are standard of care for first-line mCRPC, and no new options for this group have been approved in more than 10 years. Other PARP inhibitors like rucaparib (Rubraca) and regorafenib (Stivarga) are approved in later-line setting, but according to Shore, these therapies are needed earlier in the course of treatment. He shared real-world data from 2.500 patients with mCRPC treated in North America. The findings showed that 77% of patients received a first-line therapy, and 38% received a second-line therapy, while only 16% received a third-line therapy.

“…It is critical that we provide optimal therapies for first-line [patients with] mCRPC, as well as subsequent lines of therapy. Preventing and or delaying radiographic progression is an important clinical endpoint, as stated by Dr. Weinstock. It's important in assessing oncologic treatments and is very relevant to patients and their caregivers. By offering disease stabilization and preventing clinical progression, hallmarks of the benefit for delaying rPFS, patients will have an enhanced opportunity for additional mCRPC therapies,” stated Shore, the US chief medical officer of Surgery and Oncology, GenesisCareUSA, and director, CPI, Carolina Urologic Research Center, during the meeting.

According to Laurence Toms, MD, global clinical head, Late Development Oncology, AstraZeneca, the FDA’s concerns may subside with a closer look at the circulating tumor DNA data available from 98% of the population.

Altogether, Toms said the data show benefit in the non-BRCAm population, based on the fact that AstraZeneca defines the non-BRCAm population based on 1 single genomic test. The FDA’s definition, which requires a double-negative result on BRCA testing, is not consistent with real-world testing practices, said Toms. Typically in the real-world setting, 1 type of genomic test is available. In addition, Toms responded to the FDA’s concern of OS detriment stated that external evidence does not support the theory of OS detriment in PROpel.

In addition, Toms explained that the lack of stratification by HRR status and BRCAm status was a direct result of the standard for randomized studies at the time the trial began. He said the prospective stratification does not affect tissue test failure rate, and this practice is consistent across phase 3 randomized studies.

Regarding safety and the FDA’s concern about prolonged exposure to toxicities of olaparib, Simon Turner, PhD, executive director, Patient Safety Oncology, AstraZeneca addressed the ODAC. Turner stated that the safety profile of olaparib and abiraterone was safe and manageable with no clinically meaningful impact of health-related quality of life. He also said there is no evidence to support the prediction of substantial toxicity that could impact OS.



The decision on the future indication for olaparib in combination with abiraterone and prednisone or prednisolone followed an open public hearing during which multiple doctors expressed their views on the data supporting the sNDA and the unmet needs for patients with mCRPC. Among these speakers, there appeared to be a consensus that this regimen is needed in the space.

Rana McKay, MD

Rana McKay, MD

“Clinicians integrate the trial data, including subgroup analysis with the disease characteristics, and goals of the patient before them in clinic to select an optimal treatment strategy for a given patient, said Rana McKay, medical oncologists, and professor of medicine at UC San Diego Health, in a written statement read by a colleague during the meeting. “Patients and clinicians desire to be given the choice to select the optimal therapy based on thoughtful discussion and shared decision-making. It is critical that patients and clinicians have this choice to be able to select the best treatment regimen for the given patient based on solid clinical trial data,” McKay ended.

McKay’s opinion was seconded by E. David Crawford, MD, also of UC San Diego Health.

“The advances that have been made and a lot of diseases have been small steps. This isn't a huge step, but I agree with my colleague, Rana McKay from the San Diego that this is a step forward. It's something that we heard about that it's reasonably well tolerated. That it offers some opportunity to improve care, and that's the only goal of me goal and many of us is to see that we turned prostate cancer and chronic disease, and we're seeing that. We just need to take the steps,” said E. David Crawford, MD, a urologist and professor of Urology at UC San Diego Health.

The 11 to 1 vote by the ODAC members appeared to be based on the lack of evidence to support approval in the overall population. However, 1 member voted no to restricting the indication and another obstained from voting.

Jorge Nieva, MD

Jorge Nieva, MD

"I voted no...This is a clinical trial design and conduction in conjunction with FDA guidance on the end points. The FDA has proposed that there should be a restriction to 11% of the patient population, and I don't think this level of restriction is justified. Patients with homologous recombination deficient cancers gained significant benefits from PARP therapy and this has been seen in multiple clinical trials," said Jorge Nieva, MD, associate professor of Clinical Medicine, Keck Hospital of USC and USC Norris Cancer Hospital.

The ODAC member who obstained from voting, Ravi A. Madan, MD, senior clinician, Genitourinary Malignancies Branch, National Cancer Insitute, expressed that he was not convinced by the data from either the ITT or BRCAm population.

"The reason I have obstained is the question for the committee today provides a difficult choice to be made based on really suboptimal data from sub optimal study design. In my opinion, this is further complicated by the fact that the fundamental rationale of the combination of abiraterone and olaparib is limited and not completely supported by clinical data," said Madan.


1. Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA website. April 28, 2023. Accessed March 9, 2023. https://www.fda.gov/advisory-committees/advisory-committee-calendar/april-28-2023-meeting-oncologic-drugs-advisory-committee-meeting-announcement-04282023#event-information

Saad F, Armstrong AJ, Thiery-Vuillemin, A, et al. PROpel: Phase III trial of olaparib (ola) and abiraterone (abi) versus placebo (pbo) and abi as first-line (1L) therapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2022;40(suppl 6):11-11. doi:10.1200/JCO.2022.40.6_suppl.011.

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