AstraZeneca, Merck's Lynparza to face FDA panel in prostate cancer bid

 After several market withdrawals, the FDA’s scrutiny around the PARP inhibitor class of cancer drugs doesn't seem to be abating.

The FDA plans to gather external experts for an advisory committee meeting to review AstraZeneca and Merck & Co.’s application for Lynparza in metastatic castration-resistant prostate cancer (mCRPC), the two companies said Thursday.

The meeting of the FDA's Oncologic Drugs Advisory Committee is scheduled for April 28. The FDA’s independent advisers will review data from the phase 3 PROpel trial, which previously showed that Lynparza, in combination with Johnson & Johnson’s Zytiga, can stave off disease progression or death compared with Zytiga alone.

Based on the PROpel data, the FDA will likely have questions about whether Lynparza has proven its case in a broad mCRPC population or if the benefit is limited to a patient subgroup.

In the study, the Lynparza and Zytiga combo cut the risk of progression or death by 34% over Zytiga alone, regardless of tumor mutation status. The benefit was more pronounced in patients with homologous recombination repair (HRR) mutations, where the Lynparza regimen cut the risk by 50%.

In non-HRR mutation patients, the magnitude of benefit came in at 24%. Those data were presented at last year’s ASCO Genitourinary Cancers Symposium (ASCO GU).

More recently, AZ and Merck last month presented the final patient survival analysis. After nearly half of all patients had died in the PROpel trial, the Lynparza-Zytiga duo showed a 19% reduction in the risk of death. The improvement wasn’t statistically significant. Those in the Lynparza arm lived a median 42.1 months, versus 34.7 months in the control group, the partners said at this year’s ASCO GU meeting.

Digging into patient subgroups, investigators found that the HRR-mutated population enjoyed a wider 44% survival benefit, whereas the death risk reduction in the non-HRR group was just 11%. Even in the HRR-mutated group, those with BRCA mutations logged a large 71% death risk reduction. When those BRCA-mutated cases were excluded, the rest of the PROpel participants on Lynparza only saw a 9% death risk reduction.

While the overall survival benefit was greatest in the BRCA-mutated group, trends toward longer survival were observed across subgroups, the investigators noted.

Before the FDA raised the advisory committee hurdle, Lynparza and Zytiga won a European approval in December for mCRPC patients for whom chemotherapy isn’t clinically indicated. The go-ahead doesn't have any restrictions on tumor mutation status.

In the U.S., Lynparza boasts an mCRPC approval as a single agent following prior treatment, but only in HRR-mutated patients.

A few days ago, European drug reviewers also recommended an mCRPC approval for another PARP inhibitor, Zejula, in combination with Zytiga in a fixed-dose combination that Johnson & Johnson plans to market as Akeega. But the backing was only for BRCA-mutated tumors because that cocktail had failed to show a tumor progression benefit beyond that cancer subtype.

Meanwhile, Pfizer’s application for its PARP drug Talzenna and Xtandi in mCRPC is currently under an FDA priority review. That submission was also based on progression-free survival data as the overall survival analysis remains immature.

The FDA’s close attention to Lynparza—and the broader PARP inhibitor class—predates mCRPC. After noticing concerning signs suggesting potential harm to patients’ long-term life expectancy, the FDA last year persuaded drugmakers to pull their PARP inhibitor approvals in late-line ovarian cancer. GSK, at the FDA’s request, limited Zejula’s second-line maintenance ovarian cancer use to only cover patients with BRCA mutations.

Clovis Oncology was perhaps the most seriously hurt by the FDA’s renewed scrutiny. The company has filed for bankruptcy after withdrawing and limiting the ovarian cancer uses of Rubraca, its only commercial product.

Desperate for a new revenue stream, Clovis recently went against the FDA’s request for more mature overall survival data and petitioned the agency to approve Rubraca as a first-line maintenance therapy. The FDA has threatened to hold an advisory committee on that application.

https://www.fiercepharma.com/pharma/astrazeneca-merck-face-fda-adcom-lynparzas-prostate-cancer-bid-parp-scrutiny-escalates