Johnson & Johnson is starting the PARP inhibitor race in prostate cancer from a weak position.
Drug reviewers at the European Medicines Agency (EMA) have recommended an approval for the combination of Zejula and Zytiga for treating metastatic castration-resistant prostate cancer (mCRPC). But in a notable restriction, only patients with BRCA1/2-mutated tumors will be eligible for the drug combo after the European Commission’s expected authorization.
Johnson & Johnson, as the owner of Zytiga and Zejula in prostate cancer, plans to market the two drugs in a fixed-dose combination under the brand name Akeega. GSK holds Zejula rights in other indications.
The EMA’s recommended indication for Akeega is much narrower than the prostate cancer use for AstraZeneca and Merck’s rival PARP inhibitor, Lynparza, in its own Zytiga combo. In December, the European Commission approved Lynparza and Zytiga to treat mCRPC without any genetic mutation restrictions.
In metastatic prostate cancer, only up to about a third of cases have homologous recombination repair (HRR) gene alterations, with BRCA1/2 mutations accounting for about half of that subset, according to a Journal of Oncology study.
Akeega’s limitation stems from the combo drug's clinical trial results. In the phase 3 MAGNITUDE study, Akeega failed to top Zytiga alone in mCRPC patients without HRR alterations. In patients whose tumors carried HRR mutations, the combination therapy cut the risk of disease progression or death by 27%.
The benefit was entirely driven by those with BRCA mutations, a subgroup analysis revealed. Conversely, patients with other HRR mutations saw no improvement from the drug, according to data presented at last year’s ASCO GU meeting.
In an updated analysis shared at this year’s American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, the BRCA-mutated population again experienced better outcomes than their counterparts. After a longer follow-up, investigators noted a trend toward improvement in patient survival for Akeega in the BRCA-positive group, with a death risk reduction of 12% that hasn’t passed statistical significance. No survival difference was noted in the larger HRR-positive group.
For AZ and Merck's Lynparza, its own combination with Zytiga pared the risk of progression or death by 34% regardless of HRR status in the phase 3 PROpel trial. The improvement was 46% in the HRR-mutated group. In the final overall survival analysis shared at this year’s ASCO GU meeting, the Lynparza-Zytiga cocktail reduced the risk of death by 19% in all patients, although the number didn’t reach statistical significance.
Both Lynparza and Akeega will likely have to face a third player in mCRPC. Pfizer just reported the longest median progression-free survival for a PARP inhibitor regimen in mCRPC for its combination of Talzenna and Xtandi. The pairing’s benefit also covered all patients regardless of mutation status in a phase 3 trial. The FDA has granted priority review to Pfizer’s application in that indication, with a decision expected this year.
Meanwhile, the FDA in December pushed back a decision on AZ’s application for Lynparza in mCRPC by three months to allow it more time for a full review. As for J&J, the company hadn’t even filed the Akeega regimen with the FDA by the end of 2022, its annual securities filing shows.