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The FDA has approved the PARP inhibitor olaparib (Lynparza) in combination with abiraterone (Zytiga) for BRCA-mutated metastatic castration-resistant prostate cancer (mCRPC), the .

Adult patients should be selected for the combination therapy -- which is given with prednisone (or prednisolone) -- based on an FDA-approved companion diagnostic test to detect deleterious or suspected deleterious BRCA mutations, the agency said.

Approval was based on a subgroup analysis of the phase III PROpel trial, which randomized 796 patients with mCRPC receiving abiraterone to either olaparib or placebo. A statistically significant improvement in radiographic progression-free survival (rPFS) for the olaparib group compared with the placebo group in the intent-to-treat (ITT) population was observed.

In the exploratory subgroup analysis of 85 patients with BRCA mutations (11% of ITT population), median rPFS was not reached in the olaparib arm compared with 8 months in the placebo arm (HR 0.24, 95% CI 0.12-0.45), and overall survival (OS) was also significantly improved in these patients (HR 0.30, 95% CI 0.15-0.59).

In the 711 patients without BRCA mutations, the rPFS HR was 0.77 (95% CI 0.63-0.96), while the OS HR was 0.92 (95% CI 0.74-1.14), suggesting that the improvement in rPFS observed in the ITT population was primarily attributable to patients with BRCA mutations, the agency said.

"Preventing or delaying radiographic progression or death is an important clinical endpoint in assessing cancer treatment and is very important to patients, their caregivers, and their families," said PROpel investigator Andrew Armstrong, MD, ScM, of Duke Cancer Institute in Durham, North Carolina, in from the drugmaker.

"The PROpel results showed the Lynparza combination demonstrated a notable clinically meaningful benefit that should rapidly be considered as the standard of care treatment for patients with BRCA-mutated metastatic castration-resistant prostate cancer," he added.

Drugmakers AstraZeneca and Merck had been seeking a broader indication for the combination that would include BRCA-negative patients.

However, during a meeting of the Oncologic Drugs Advisory Committee in April, the panel recommended against it, explaining that they had issues with PROpel's trial design, since it did not include a prospective analysis plan for efficacy results by biomarker status, in addition to the fact that the study did not explicitly demonstrate a benefit for patients without BRCA mutations.

The most common adverse reactions (≥10%) in patients receiving olaparib plus abiraterone were anemia (48%), fatigue (38%), nausea (30%), diarrhea (19%), decreased appetite (16%), lymphopenia (14%), dizziness (14%), and abdominal pain (13%). Eighteen percent of patients in PROpel required at least one blood transfusion, and 12% required multiple transfusions.

The recommended olaparib dosage is 300 mg taken orally twice daily with or without food. The recommended abiraterone dose is 1,000 mg taken orally once daily. Abiraterone should be administered with prednisone or prednisolone 5 mg orally twice daily. Patients should also receive a GnRH analog concurrently, or should have had a prior bilateral orchiectomy.

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