Pfizer's drug combination of Talzenna and Xtandi helped patients with first-line metastatic castration-resistant prostate cancer live longer compared with Xtandi alone.
Pfizer hopes a unique life-extension benefit for its Talzenna can serve to further expand the drug’s already broadest-in-class U.S. label in prostate cancer.Following an FDA approval in 2023 that allows Talzenna to be used with Pfizer’s Astellas-partnered Xtandi to treat metastatic castration-resistant prostate cancer (mCRPC) cases that have homologous recombination repair (HRR) gene mutations, updated phase 3 data now show that the regimen can extend lives in an unselected patient population—regardless of biomarker status.The Talzenna-Xtandi combo led to a statistically significant 20.4% reduction the risk of death compared with Xtandi alone in first-line mCRPC, according to the final overall survival analysis from the TALAPRO-2 trial presented at the ASCO Genitourinary Cancers Symposium.The two-drug regimen extended the median time patients lived by 8.8 months to 45.8 months, investigators said.Naturally, the focus for this data drop is on patients without HRR gene alterations, as they’re not covered in the combo’s existing U.S. label. In patients whose tumors were HRR-non-deficient or unknown, Talzenna-Xtandi showed a smaller but still favorable 12.6% improvement in the risk of death.Among those confirmed to have no HRR alterations based on both circulating tumor DNA (ctDNA) and tumor tissue samples, the Talzenna-Xtandi duo mounted a 21.8% overall survival benefit versus Xtandi. In this group, the combo’s 9.2-month longer median survival time reached 46.6 months.HRR-deficient tumors only make up about 25% of mCRPC cases. This breakdown is reflected in the TALAPRO-2 study, which enrolled about three-quarters of participants with HRR-non-deficient or unknown status.Even with an FDA nod covering all HRR mutations, PARP inhibitors like Talzenna are known to work best in the subtype of BRCA mutations. In TALAPRO-2, patients with no BRCA alterations—as detected by both ctDNA and tumor tissues—enjoyed a 25.1% reduction in the risk of death while on Talzenna and Xtandi.“We see that this benefit is really consistent, regardless of the subgroups that are evaluated,” Dana Kennedy, Pfizer’s genitourinary cancers development head, said in an interview with Fierce Pharma. “We see that median [overall survival] around 45 months in our gene-altered patients, as well as those patients who lack HRR gene alterations.” PARP inhibitors have historically been able to show some tumor progression benefits, but these benefits haven’t always translated into longer patient life spans thanks in part to nasty side effects. In TALAPRO-2, treatment-related serious adverse events were notably more frequent, at 21.4%, in the Talzenna-Xtandi arm than the 3.2% rate seen in the Xtandi group. Anemia was the most common treatment-emergent adverse event, with rates of 67.8% and 20%, respectively, in the two arms.Anemia is not a cumulative toxicity for the combo, Kennedy noted. Cases typically arose early in the course of treatment, and patients were mostly able to stay on treatment with dose modifications or interruptions. All told, 21.6% of patients discontinued Talzenna due to any adverse events in the combo arm, including a fewer than 10% rate of discontinuations from anemia, according to Kennedy.The other concern for Pfizer is whether doctors will paint all PARP inhibitors with the same brush. Back in 2023, the FDA gave Johnson & Johnson’s Akeega—a fixed tablet of GSK’s PARP inhibitor Zejula and J&J’s Zytiga—and AstraZeneca and Merck’s Lynparza-Zytiga cocktail separate approvals that limit their mCRPC uses to BRCA mutations only.In addition, in ovarian cancer, the largest market for PARP inhibitors, cases with BRCA mutations are driving the majority of PARP adoption despite the larger non-BRCA-mutated patient base.Kennedy acknowledged that the other two PARP drugs’ results might impact the scientific community’s view of Talzenna. But she argued that Pfizer’s data set is differentiated because it’s the only one that now boasts an overall survival win in a biomarker-agnostic group. Besides, Talzenna is being paired with Xtandi, an androgen receptor inhibitor, rather than Zytiga, which is an androgen biosynthesis inhibitor, the Pfizer exec said.Despite approvals in HRR-deficient mCRPC and BRCA-mutated breast cancer, Talzenna only brought in $88 million in U.S. sales in 2024. Outside of the PARP class, Talzenna will probably need to compete with Novartis’ radioligand therapy Pluvicto, which is under FDA review for first-line mCRPC.The updated overall survival results from the phase 3 PSMAfore trial supporting Novartis’ filing have yet to be published. Still, Kennedy noted that PSMAfore and TALAPRO-2 enrolled different patient populations. The Novartis study was specifically in patients who had received prior novel hormonal therapy (NHT) before the mCRPC stage and randomized them to receive a switch of NHT or Pluvicto. The Pfizer trial included patients who had no prior exposure to an NHT.
