Johnson & Johnson's PARP combo nabs first global nod but faces tough fight against AZ, Merck's Lynparza

Johnson & Johnson’s idea to carve out the prostate cancer indication from GSK’s PARP inhibitor Zejula has yielded its first global approval.

Following a recommendation from the European Medicines Agency, the European Commission has officially approved J&J’s Akeega in metastatic castration-resistant prostate cancer (mCRPC), J&J said Friday. The drug is a fixed-dose combo of Zejula and J&J’s androgen-directed Zytiga, and it’s used alongside a corticosteroid.

Under a 2016 deal with Zejula’s developer Tesaro, J&J specifically carved out rights to the drug in prostate cancer. GSK then bought out Tesaro in 2019.

Not all patients can get Akeega under the drug’s European label. To be eligible, a patient’s tumor must test positive for BRCA1/2 mutations, which account for 10% to 15% of all cases, J&J said.

Akeega’s label in Europe is narrower than that of rival PARP inhibitor Lynparza from AstraZeneca and Merck. The European Commission in December cleared Lynparza and Zytiga for mCRPC with no restrictions on tumor mutation status.

Akeega got the narrow indication despite showing a tumor progression benefit in a larger group of patients with various mutations in homologous recombination repair (HRR) genes.

In the phase 3 Magnitude study, Akeega reduced the risk of radiographic disease progression or death by 27% in HRR-positive patients. But the benefit was mostly driven by the BRCA-mutant subgroup, which saw a 47% reduction on the same marker.

After a longer follow-up of about two years, investigators also observed a trend suggesting Akeega can extend the lives of patients with BRCA mutations but not in the larger HRR-positive group.

Also in Magnitude, Akeega failed to show a benefit in HRR-negative patients. By comparison, the Lynparza-Zytiga combo delivered a 34% risk reduction in disease progression or death in the phase 3 PROpel trial covering all patients regardless of their HRR status. As expected, the benefit was also more pronounced in the HRR-positive cohort.

Despite the broad approval in Europe, Lynparza faces an extra FDA hurdle in the U.S. The FDA is gathering its external oncology advisers in a public meeting this Friday to discuss Lynparza’s mCRPC application.

Subgroup analyses will likely become a key focus for FDA’s review. Some earlier clinical trials suggested that PARP inhibitors, including Lynparza, might cause harm to late-line ovarian cancer patients over the long term despite an initial ability to prevent cancer from progressing. The red flag has prompted FDA scrutiny on the entire PARP inhibitor class, and companies have limited their drugs’ use in patient groups where the benefit didn’t seem to outweigh the risk.

As for Akeega, J&J said it submitted an application with the FDA in February seeking approval for BRCA-positive mCRPC.

Meanwhile, a third player, Pfizer, has an FDA priority review for its proposed PARP-ARi combination of Talzenna and Xtandi in mCRPC, with a decision now expected this year. To date, that combo has produced the longest median progression-free survival among the three regimens in a broad mCRPC population.