Pfizer’s talazoparib-enzalutamide combination moves to earlier line in prostate cancer, with eligibility tied to genetic testing and immature survival data.
The FDA today expanded the approval of Talzenna (talazoparib) plus Xtandi (enzalutamide) to men with metastatic prostate cancer that has not been treated with androgen pathway drugs, or remains sensitive to them, and that carries homologous recombination repair (HRR) gene mutations, according to Pfizer.1
The regimen, first cleared in 2023 for castration-resistant disease, now reaches an earlier stage of treatment, with eligibility depending on a positive biomarker test.2 For Pfizer, the decision moves a combination the company describes as an established standard-of-care option into an earlier line of therapy, where it says more patients may experience benefit.
Aamir Malik, executive vice president and chief U.S. commercial officer at Pfizer, said in the announcement: “Today’s approval of Talzenna plus Xtandi builds on its established role as a standard-of-care option for men with advanced prostate cancer. Moving this targeted therapy into the androgen pathway modulation-naïve or -sensitive setting further reflects our commitment to men with HRR-mutated metastatic prostate cancer, providing a new option at a stage where it may have a greater impact to delay progression.”1
The label covers adults whose tumors carry HRR mutations detected by an FDA-authorized test, spanning 12 genes rather than BRCA1 and BRCA2 alone.2 Two previously approved FoundationOne assays, one using tumor tissue and one using a liquid biopsy, can identify eligible patients.2
The recommended Talzenna dose is 0.5 mg orally once daily with Xtandi until progression or unacceptable toxicity, alongside androgen deprivation therapy.2 The agency granted priority review and conducted the assessment under Project Orbis, a framework for concurrent oncology reviews with international regulators.2
TALAPRO-3 randomized 599 patients with HRR-mutated disease to Talzenna 0.5 mg or placebo daily, each combined with Xtandi 160 mg.1 The primary endpoint was investigator-assessed radiographic progression-free survival.1
Talzenna plus Xtandi reduced the risk of radiographic progression or death by 52% (hazard ratio, 0.48; 95% confidence interval, 0.36–0.65; P < .0001), with consistent benefit across BRCA and non-BRCA mutations.1 Median radiographic progression-free survival was not reached in the Talzenna versus 45.8 months with placebo plus Xtandi.2
Pfizer estimates that 77% of patients remained progression-free at three years.1 The results were published in The New England Journal of Medicine.3
Pfizer reported no new safety signals. The most common grade 3 or higher adverse event was anemia, affecting 51% of the talazoparib group and 3% of controls, and 5% of patients stopped talazoparib because of anemia.1
Pfizer says about 25% of patients with hormone-sensitive metastatic prostate cancer have HRR mutations.1
Neeraj Agarwal, M.D., global lead investigator for TALAPRO-3, said: “This approval represents a critical advancement for patients with newly diagnosed metastatic prostate cancer with HRR gene mutations, who face a more aggressive disease, worse prognosis, and limited treatment options. In the TALAPRO-3 trial, clinical benefits were consistent for patients with BRCA and non-BRCA HRR gene mutations, addressing a long-standing unmet need – and reinforcing the importance of biomarker testing at the time of diagnosis.”1
Because eligibility requires a positive test, the number of patients who receive the regimen will depend partly on how consistently genotyping occurs at diagnosis.
Talzenna was first approved as a single agent for certain germline BRCA-mutated breast cancers. The FDA cleared the combination in June 2023 for HRR-mutated castration-resistant prostate cancer, and the European Commission followed in January 2024 for castration-resistant disease in patients for whom chemotherapy is not clinically indicated.1
Pfizer says the combination is approved in more than 60 countries, with indications varying by country.1 The castration-resistant approval rested on TALAPRO-2, in which unselected patients had a hazard ratio of 0.63 for progression or death with Talzenna plus Xtandi versus placebo plus enzalutamide.4
Overall survival data were immature at the time of the analysis, and the FDA announcement did not report survival estimates.2 Pfizer’s own risk disclosures list whether TALAPRO-3 will meet its key secondary overall survival endpoint as an uncertainty.1
Because the Talzenna arm has not reached median radiographic progression-free survival, the absolute difference between arms is not yet defined, and the 45.8-month control median indicates that Xtandi alone also provides prolonged disease control in this population.2 The primary endpoint also relied on investigator assessment, which can differ from blinded independent review.1
Prescribing information carries warnings for myelodysplastic syndrome and acute myeloid leukemia, with a cumulative incidence of about 1% across talazoparib studies, as well as myelosuppression requiring monthly blood count monitoring and embryo-fetal toxicity.1
The European Medicines Agency is reviewing the same indication.1
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