First-line talazoparib with enzalutamide in HRR-deficient metastatic castration-resistant prostate cancer: The phase 3 TALAPRO-2 trial

Fizazi, K. et al. (2023) First-line talazoparib with enzalutamide in HRR-deficient metastatic castration-resistant prostate cancer: The phase 3 TALAPRO-2 trial. Nature Medicine, 30, pp. 257-264. (doi: 10.1038/s41591-023-02704-x) (PMID:38049622) (PMCID:PMC10803259)

Abstract

Preclinical evidence has suggested an interplay between the androgen receptor, which largely drives the growth of prostate cancer cells, and poly(ADP-ribose) polymerase. This association provides a rationale for their co-inhibition for the treatment of metastatic castration-resistant prostate cancer (mCRPC), an area of unmet medical need. The phase 3 TALAPRO-2 study investigated combining the poly(ADP-ribose) polymerase inhibitor talazoparib with enzalutamide versus enzalutamide alone as first-line treatment of mCRPC. Patients were prospectively assessed for tumor alterations in DNA damage response genes involved in homologous recombination repair (HRR). Two cohorts were enrolled sequentially: an all-comers cohort that was enrolled first (cohort 1; N = 805 (169 were HRR-deficient)), followed by an HRR-deficient-only cohort (cohort 2; N = 230). We present results from the alpha-controlled primary analysis for the combined HRR-deficient population (N = 399). Patients were randomized in a 1:1 ratio to talazoparib or placebo, plus enzalutamide. The primary endpoint, radiographic progression-free survival, was met (median not reached at the time of the analysis for the talazoparib group versus 13.8 months for the placebo group; hazard ratio, 0.45; 95% confidence interval, 0.33 to 0.61; P < 0.0001). Data for overall survival, a key secondary endpoint, are immature but favor talazoparib (hazard ratio, 0.69; 95% confidence interval, 0.46 to 1.03; P = 0.07). Common adverse events in the talazoparib group were anemia, fatigue and neutropenia. Combining talazoparib with enzalutamide significantly improved radiographic progression-free survival in patients with mCRPC harboring HRR gene alterations, supporting talazoparib plus enzalutamide as a potential first-line treatment for these patients.

• Item Type: Articles
• Additional Information: This study was sponsored by Pfizer Inc.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Jones, Professor Robert
• Authors: Fizazi, K., Azad, A. A., Matsubara, N., Carles, J., Fay, A. P., De Giorgi, U., Joung, J. Y., Fong, P. C. C., Voog, E., Jones, R. J., Shore, N. D., Dunshee, C., Zschäbitz, S., Oldenburg, J., Ye, D., Lin, X., Healy, C. G., Di Santo, N., Laird, A. D., Zohren, F., and Agarwal, N.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Medicine
• Publisher: Nature Research
• ISSN: 1078-8956
• ISSN (Online): 1546-170X
• Copyright Holders: Copyright: © The Author(s) 2023, corrected publication 2024
• First Published: First published in Nature Medicine 30: 257-264
• Publisher Policy: Reproduced under a Creative Commons licence