FDA Staff Not Sold on Broad Olaparib Indication in Metastatic CRPC

Olaparib (Lynparza) plus abiraterone (Zytiga) as initial treatment for metastatic castration-resistant prostate cancer (CRPC) is only clearly effective in patients with BRCA mutations, FDA staff contended in a briefing document released ahead of an advisory committee meeting.

On Friday, the FDA is asking its Oncologic Drugs Advisory Committee (ODAC) to weigh in on whether a proposed indication in this patient population should be restricted to the BRCA-positive subset. However, AstraZeneca, developer of the PARP inhibitor olaparib, is seeking a broad indication for the combination treatment that would include BRCA-negative patients and those without homologous recombination repair (HRR) mutations.

Agency reviewers indicated concerns that the primary support for the application -- the PROpel trial -- did not demonstrate the efficacy and safety of the treatment outside of patients with BRCA mutations, "and that the addition of olaparib to abiraterone may cause harm in patients who are definitively negative for tumor BRCA mutations."

The phase III trial met its primary endpoint, showing a significant radiographic progression-free survival improvement with olaparib plus abiraterone, at 24.8 months versus 16.6 months with placebo plus abiraterone (HR 0.66, 95% CI 0.54-0.81, P<0.0001).

An overall survival (OS) analysis further demonstrated a trend favoring the olaparib-treated group (HR 0.81, 95% CI 0.67-1.00).

PROpel enrolled an intent-to-treat (ITT) population that "neither prospectively assessed BRCA or HRR status nor included prespecified analyses for these subgroups," FDA staff noted.

"Based on contemporary understanding of the importance of BRCA status as a predictive biomarker for PARP inhibitor efficacy, this trial design would be considered inappropriate today as the biomarker should have been prospectively evaluated," they wrote. "Additionally, a prospective analysis plan for efficacy results should have been formulated, for example with stratification or enrollment into separate cohorts by biomarker status. This is a significant design flaw that other sponsors designing similar studies have more appropriately addressed."

Post hoc analyses performed by the agency showed that the BRCA-positive group, which made up just 11% of the ITT population, nonetheless drove the bulk of any potential OS benefit:

• BRCA-positive: HR 0.30 (95% CI 0.15-0.60)
• BRCA-uncertain: HR 0.73 (95% CI 0.52-1.03)
• BRCA-negative: HR 1.06 (95% CI 0.81-1.39)

"The addition of olaparib to abiraterone in patients with a high likelihood of no BRCA mutations (negative by two assays), which constituted the majority of patients in the ITT population, potentially results in a detriment in OS," FDA staff observed.

Moreover, they noted that the results are consistent with studies of PARP inhibitors in prostate cancer and other tumor types, and pointed out that the maintenance indications for other PARP inhibitors in metastatic ovarian cancer were recently restricted due to concerns of an OS detriment in patients without BRCA mutations.

In AstraZeneca's briefing document, the company acknowledged the difference between subgroups but made the case that PROpel was a positive study overall and that the benefit-risk profile was "also positive" in patients without BRCA mutations, supporting the broader indication. The company said that it would be important to inform prescribers of the differences between the subgroups, and proposed including relevant biomarker subgroup data in the U.S. prescribing information.

While the FDA is not required to follow the advice of its advisory committees, it typically does.

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