First-line talazoparib with enzalutamide in HRR-deficient metastatic castration-resistant prostate cancer: the phase 3 TALAPRO-2 trial
Details
Publication Year 2024-01,Volume 30,Issue #1,Page 257-264
Journal Title
Nature Medicine
Publication Type
Research article
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. ClinicalTrials.gov Identifier: NCT03395197 .
Publisher
Springer Nature
Keywords
Male; Humans; *Prostatic Neoplasms, Castration-Resistant/drug therapy/genetics; Recombinational DNA Repair; *Antineoplastic Agents/therapeutic use; Nitriles; *Benzamides; *Phenylthiohydantoin; *Phthalazines
Department(s)
Medical Oncology
Open Access at Publisher's Site
https://doi.org/10.1038/s41591-023-02704-x
Terms of Use/Rights Notice
Refer to copyright notice on published article.


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