- Published in The Lancet, final overall survival results of the phase 3 TALAPRO-2 trial show that talazoparib plus enzalutamide significantly improves survival in patients with homologous recombination repair-deficient metastatic castration-resistant prostate cancer, especially in those with BRCA1/2 alterations.
- This new drug combination reduced the risk of death by 38%, with a median overall survival of 45.1 months compared to 31.1 months with standard treatment. This is the first combination of a PARP inhibitor and an androgen receptor pathway inhibitor to show a statistically significant clinical benefit, further supporting this strategy as a new standard of care for this high-risk population.
Recently published in The Lancet1, final overall survival results of part 2 of the multi-center, international phase 3 TALAPRO-2 trial demonstrate that the combination of poly ADP ribose polymerase inhibitor (PARPi) talazoparib plus androgen receptor pathway inhibitor (ARPI) enzalutamide, resulted in statistically significant and clinically meaningful improvement in overall survival versus standard of care enzalutamide plus placebo in patients with metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) gene alterations.
With an estimated 1.5 million new cases and 397,000 deaths worldwide in 2022, prostate cancer ranks second as the most frequent cancer globally and the fifth leading cause of cancer death among men2. mCRPC is a cancer that has spread beyond the prostate gland and has progressed despite medical or surgical treatment to lower testosterone. Between around 10 and 20% of patients with prostate cancer develop castration-resistant disease within around 5 years of follow-up.
Conducted at 142 hospitals, cancer centers, and medical centers in 26 countries, this two-part study was designed to evaluate the efficacy of the combination in patients with mCRPC whose tumor samples were prospectively assessed for HRR gene alterations, and to compare results without selecting patients with this genomic profile.
Presented at the 2025 ASCO Genitourinary Cancers Symposium, February 13-15 in San Francisco, results of final overall analysis of TALAPRO-2 in patients unselected for alterations in DNA damage repair genes (part 1 of the study), showed that the investigational combination increased overall survival by 8.8 months and reduced the risk of death by 20.4%.
Co-authored by Joan Carles, a Medical Oncologist at the Vall d’Hebron University Hospital and co-lead of VHIO’s Prostate Cancer Group, the investigators have now reported final overall survival results in patients selected for HRR gene alterations.
This second part of the study included 399 patients with HRR-deficient mCRPC, half of whom (200) were randomly assigned were randomly assigned to talazoparib plus enzalutamide, and the other half (199) received enzalutamide plus placebo. At a median follow-up of 44.2 months, treatment with the new drug combination resulted in a statistically significant improvement in overall survival versus enzalutamide, with a median overall survival of 45.1 months in the talazoparib group versus 31.1 months in the control group, and a 38% reduction in the risk of death in patients assigned to talazoparib plus enzalutamide.
“To-date, talazoparib plus enzalutamide is the only PARPi and ARPI combination to have demonstrated a statistically significant improvement in overall survival compared to ARPI monotherapy in patients with HRR-deficient metastatic castration-resistant prostate cancer. Our results show a longer median overall survival compared to studies with current standard therapies including docetaxel, ARPIs, and PARPi plus ARPI combinations, both in patients with HRR deficiency and in unselected patients with mCRPC,” observed Joan Carles.
The findings confirm consistent benefits of the treatment combination across different clinical subgroups, particularly in those patients with BRCA1/2 gene alterations, with a 50% reduction in the risk of death compared to standard treatment with enzalutamide alone. While the median overall survival was not reached, 4-year overall survival rates in these patients were 53% in the talazoparib group versus 23% in the control group.
“In addition to the results that we reported at ASCO GU, our data further support this combination therapy as a new standard of care in HRR-deficient metastatic castration-resistant prostate cancer, especially in those patients with BRCA1/2 alterations,” concluded Carles.
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References
- Fizazi K, Azad AA, Matsubara N, Carles J, Fay AP, De Giorgi U, Young Joung J, Fong PCC, Voog E, Jones RJ, Shore ND, Dunshee C, Zschäbitz S, Oldenburg J, Ye D, Lin X, Kalac M, Douglas Laird A, Kennedy D, Agarwal N. Talazoparib plus enzalutamide in men with HRR-deficient metastatic castration-resistant prostate cancer: final overall survival results from the randomised, placebo-controlled, phase 3 TALAPRO-2 trial. Lancet. 2025 Jul 16:S0140-6736(25)00683-X. doi: 10.1016/S0140-6736(25)00683-X. Epub ahead of print.
- Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024 May-Jun;74(3):229-263.
