The FDA has already approved PARP inhibitors in certain patients with metastatic castration-resistant prostate cancer (mCRPC). Now, Johnson & Johnson’s Akeega is giving the class a win in castration-sensitive disease, although the drug’s benefit in a patient subgroup remains unclear.

In patients with metastatic castration-sensitive prostate cancer (mCSPC) with homologous recombination repair (HRR), Akeega and prednisone significantly reduced the risk of tumor progression or death by 37% versus J&J’s Zytiga and prednisone, according to data shared at the 2025 American Society of Clinical Oncology annual meeting. Akeega is a fixed-dose combination of GSK’s PARP inhibitor Zejula—to which J&J owns prostate cancer rights—and Zytiga.

Despite the positive readout from the phase 3 Amplitude trial, saying Akeega has a clear regulatory path ahead in all HRR-mutated mCSPC would be too optimistic.

The uncertainty lies in a group of patients without BRCA mutations.

Previously, Zejula’s addition to Zytiga and prednisone showed a progression-free survival benefit in HRR-mutated mCRPC in the phase 3 Magnitude trial. But after speaking with the FDA and realizing that the drug was most beneficial in the BRCA-mutated population, J&J filed for—and received—an approval only in that subset of patients. 

Now, Amplitude is facing the same BRCA/non-BRCA question.

Compared with the entire trial population, the Akeega regimen’s magnitude of progression-free survival benefit was notably bigger at 48% in the BRCA-mutated subgroup.

“The benefit may be greatest in patients with BRCA alterations,” lead study author Gerhardt Attard, M.D., Ph.D., from University College London, said during a press briefing.

The result is still in favor of Akeega in the non-BRCA subgroup, with an improvement of around 20%, Attard noted.

“There is efficacy in the non-BRCA subgroup,” Attard said. “It’s heterogeneous, and it’s a number of different smaller gene subgroups.”

“You’re going to need to do meta-analysis of multiple different trials to have certainty which subgroup has clear evidence of efficacy.”

The non-BRCA subgroup is not small, accounting for 45% of the Amplitude population.

Based on the current data, Akeega doesn’t appear to work in patients with the PALB2 mutation, but there are positive trends in other subtypes, Mark Wildgust, Ph.D., vice president of oncology global medical affairs at J&J Innovative Medicine, said in an interview with Fierce Pharma.

“Does it have the same magnitude [of benefit as in BRCA]? I do not believe it does,” Wildgust said. “Is there enough there for regulatory approval? Maybe not right now, but maybe in the future. Maybe we have to wait a bit longer to see longer-term follow up and to understand the question.”

J&J will have a discussion with global regulators, including the FDA, on whether the Amplitude trial has shown a positive risk-benefit profile in the overall HRR population, Wildgust said.

Besides progression-free survival, researchers also identified a positive trend toward improved overall survival in the Akeega arm. However, data here were immature and didn’t meet statistical significance at the current analysis. The preliminary death reduction was 25% in the BRCA-mutated group and 21% in the overall trial population.

Editor's Note: The story was updated to clarify the situation around Akeega's mCRPC indication.