Final Analysis of TALAPRO-2 in mCRPC Confirms Significant Benefit

The final overall survival (OS) analysis of the phase 3 TALAPRO-2 trial (NCT03395197) has shown that the addition of talazoparib (Talzenna) to enzalutamide (Xtandi) significantly improved OS in a broad population of patients with metastatic castration-resistant prostate cancer (mCRPC), including those without documented homologous recombination repair (HRR) gene alterations.¹

The findings, published in The Lancet, provide strong evidence for this combination therapy as a new standard-of-care initial treatment for this patient group. The trial's findings are particularly notable for demonstrating a robust OS benefit in a genetically unselected cohort, addressing a key question about the applicability of this approach beyond patients with HRR-deficient tumors.

The TALAPRO-2 study enrolled 805 patients with mCRPC who were randomly assigned to receive either the combination of talazoparib plus enzalutamide or placebo plus enzalutamide. With a median follow-up of 44.8 months, the combination arm demonstrated a median OS of 45.8 months compared with 37.0 months in the placebo arm, representing a statistically significant improvement with a hazard ratio of 0.80. This translated to a 4-year survival rate of 48% for patients on the combination therapy vs 38% for those in the control group.

A key aspect of the trial's design was its inclusion of a genetically unselected patient population. While PARP inhibitors like talazoparib have shown significant efficacy in patients with documented HRR gene alterations, their benefit in a broader, unselected population has been less clear. The TALAPRO-2 results provide compelling evidence that the synergistic effects of talazoparib and enzalutamide extend beyond the HRR-deficient subgroup. In a prespecified subgroup analysis, the OS benefit was even more pronounced in patients with HRR-deficient alterations (HR, 0.55), but a meaningful, though smaller, benefit was also observed in patients without or with unknown alterations (HR, 0.88).

These data build upon previously reported results showing a significant improvement in radiographic progression-free survival (rPFS). With extended follow-up, the median rPFS was 33.1 months in the combination group compared with 19.5 months in the control arm. The consistent and sustained benefit across both rPFS and now OS reinforces the therapeutic value of this regimen.

The combination of an androgen receptor (AR) inhibitor like enzalutamide and a PARP inhibitor like talazoparib is thought to provide a dual mechanism of action, targeting both the hormonal signaling pathway and DNA damage repair pathways that are often compromised in prostate cancer.

The safety profile of the combination therapy was consistent with previously reported data. While the addition of talazoparib did lead to a higher incidence of certain adverse events, particularly hematologic toxicities such as anemia, these were generally manageable with dose modifications and supportive care. The long-term safety and tolerability of the regimen, as demonstrated by the final analysis, support its use as a viable and effective treatment option.

About Talazoparib and TALAPRO-2

In June 2023, the FDA approved talazoparib plus enzalutamide in patients with HRR gene mutations.²

In May 2025, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted unanimously that data from TALAPRO-2 were insufficient to conclude a favorable benefit-risk profile for adding talazoparib to enzalutamide in the non-HRR–mutation population.³ In the meeting, ODAC members expressed concerns over a lack of a prespecified, statistically powered analysis in the non-HRR–mutation subgroup.

REFERENCES:

1. Agarwal N, Azad AA, Carles J, et al. Talazoparib plus enzalutamide in men with metastatic castration-resistant prostate cancer: final overall survival results from the randomised, placebo-controlled, phase 3 TALAPRO-2 trial. Lancet. 2025 Aug 2;406(10502):447-460. doi: 10.1016/S0140-6736(25)00684-1. Epub 2025 Jul 16.

2. Pfizer’s TALZENNA® in combination with XTANDI® receives U.S. FDA approval. News release. Pfizer. June 20, 2023. Accessed August 12, 2025. https://tinyurl.com/y9vahdu3

3. Meeting of the Oncologic Drug Advisory Committee. FDA. May 21, 2025. Accessed August 12, 2025. https://tinyurl.com/5n7mwvjt