The PARP inhibitor class is welcoming its second FDA approval in prostate cancer in the span of several weeks. The new approval, for Pfizer, is broader than the first but still limited.
The FDA has greenlighted Pfizer’s Talzenna, in combination with the company’s Astellas-partnered Xtandi, to treat metastatic castration-resistant prostate cancer (mCRPC) that has homologous recombination repair (HRR) gene mutations.
Talzenna’s approval comes three weeks after AstraZeneca and Merck’s Lynparza got its own front-line mCRPC approval for use alongside Johnson & Johnson’s Zytiga. But that approval only covers patients whose tumors have BRCA mutations. BRCA is part of the HRR family.
By Pfizer’s estimate, HRR gene mutations account for about 25% of mCRPC cases. BRCA mutations make up about 10% of the entire mCRPC population.
Talzenna looks to have the PARP class’s widest mCRPC label in the U.S. for quite some time. Another potential rival, Johnson & Johnson, is applying for FDA approval for a combo of niraparib—sold as Zejula by GSK outside prostate cancer—and Zytiga, but only in BRCA-mutant disease.
For its part, Pfizer remains hopeful that longer-term data can help it secure an even broader indication in mCRPC regardless of genetic mutation status.
The FDA has been extra careful when reviewing PARP inhibitors after having asked drugmakers to cut back their existing ovarian cancer approvals. The concerns stem from long-term clinical data suggesting these drugs’ efficacy may only outweigh their risks in BRCA-mutant or HRR-mutant cancers.
Talzenna's current approval was based on the phase 3 TALAPRO-2 trial. In cohort 1, which enrolled patients with or without HRR mutations, adding Talzenna to Xtandi reduced the risk of tumor progression or death by 37%, according to results shared at the at the American Society of Clinical Oncology Genitourinary Cancers Symposium in February.
But the actual approval only covers HRR-mutant patients. A pooled analysis of HRR-mutant patients in cohort 1 and the HRR-mutant-only cohort 2 linked the Talzenna-Xtandi combo to a 55% improvement in progression-free survival over Xtandi alone, according to results presented at the ASCO annual meeting earlier this month.
The FDA previously gave AZ and Merck's Lynparza a BRCA-mutant-only approval. An FDA analysis of the phase 3 PROpel trial suggested that the AZ/Merck drug might hurt patients’ survival despite a tumor progression benefit in those without BRCA mutations. And the FDA wasn’t sure about the drug’s performance in other HRR alternations because of a trial design flaw.
Talzenna’s patient survival data are still immature and were trending in the PARP inhibitor’s favor for the overall trial population, according to investigators. But the FDA clearly wants to see more before signing off on a label covering the non-HRR subgroup.
Based on how the trial has progressed, the overall survival (OS) readout is expected to mature in 2024, Neeraj Agarwal, M.D., from the University of Utah and lead investigator of TALAPRO-2, told Fierce Pharma in an interview. He declined to describe how OS is trending now for the non-HRR patients.
“If the combination demonstrates an OS benefit, Pfizer intends to file for potential approval in the all-comers population,” a Pfizer spokesperson told Fierce Pharma.
For now, data for Talzenna in other non-BRCA HRR mutations have given the FDA enough confidence to grant the current nod. In those patients, the Talzenna combo has so far shown a progression-free survival improvement of 28% and a 29% reduction in the risk of death.
Because of the toxicities of adding a PARP inhibitor on top of other agents, some experts have suggested that these drugs should be used sequentially rather than in combinations. Before the combination approvals, Lynparza monotherapy was approved in previously treated HRR-mutated mCRPC.
Agarwal argued that because tumors are typically made up of different types of cells, targeting multiple mechanisms at the same time can help with outcomes. He also pointed to real-world studies that suggest about 40% of 50% patients didn’t get to their second line of treatment because of disease progression.
“That’s the most concrete rationale for using combination, or I call it intensification therapy, because you’re going to be denying therapy to half of those patients,” Agarwal said.
Beyond mCRPC, Pfizer and Astellas are testing Talzenna with Xtandi in HRR-mutated metastatic hormone-sensitive prostate cancer, with an anticipated primary completion date for that trial in late 2024.