Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial

• Published in: The Lancet (British edition) 2023-07, Vol.402 (10398), p.291-303
• Main Authors: Agarwal, Neeraj, Azad, Arun A, Carles, Joan, Fay, Andre P, Matsubara, Nobuaki, Heinrich, Daniel, Szczylik, Cezary, De Giorgi, Ugo, Young Joung, Jae, Fong, Peter C C, Voog, Eric, Jones, Robert J, Shore, Neal D, Dunshee, Curtis, Zschäbitz, Stefanie, Oldenburg, Jan, Lin, Xun, Healy, Cynthia G, Di Santo, Nicola, Zohren, Fabian, Fizazi, Karim
• Format: Article
• Language: English
• Subjects: Adenosine diphosphate; Adolescent; Androgen Antagonists - therapeutic use; Androgen receptors; Androgens; Anemia; Anemia - drug therapy; Anticancer properties; Antineoplastic Combined Chemotherapy Protocols; Castration; Clinical trials; DNA damage; DNA repair; Double-Blind Method; Double-blind studies; Effectiveness; Genes; Health care facilities; Health services; Homologous recombination; Homologous recombination repair; Humans; Industrialized nations; Male; Metastases; Metastasis; Mortality; Neutropenia; Oral administration; Patients; Placebos; Poly(ADP-ribose); Poly(ADP-ribose) polymerase; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - genetics; Randomization; Receptors; Receptors, Androgen; Ribose; Safety; Statistical analysis; Survival; Therapy; Tumors
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/S0140-6736(23)01055-3

Co-inhibition of poly(ADP-ribose) polymerase (PARP) and androgen receptor activity might result in antitumour efficacy irrespective of alterations in DNA damage repair genes involved in homologous recombination repair (HRR). We aimed to compare the efficacy and safety of talazoparib (a PARP inhibitor) plus enzalutamide (an androgen receptor blocker) versus enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC). TALAPRO-2 is a randomised, double-blind, phase 3 trial of talazoparib plus enzalutamide versus placebo plus enzalutamide as first-line therapy in men (age ≥18 years [≥20 years in Japan]) with asymptomatic or mildly symptomatic mCRPC receiving ongoing androgen deprivation therapy. Patients were enrolled from 223 hospitals, cancer centres, and medical centres in 26 countries in North America, Europe, Israel, South America, South Africa, and the Asia-Pacific region. Patients were prospectively assessed for HRR gene alterations in tumour tissue and randomly assigned (1:1) to talazoparib 0·5 mg or placebo, plus enzalutamide 160 mg, administered orally once daily. Randomisation was stratified by HRR gene alteration status (deficient vs non-deficient or unknown) and previous treatment with life-prolonging therapy (docetaxel or abiraterone, or both: yes vs no) in the castration-sensitive setting. The sponsor, patients, and investigators were masked to talazoparib or placebo, while enzalutamide was open-label. The primary endpoint was radiographic progression-free survival (rPFS) by blinded independent central review, evaluated in the intention-to-treat population. Safety was evaluated in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (NCT03395197) and is ongoing. Between Jan 7, 2019, and Sept 17, 2020, 805 patients were enrolled and randomly assigned (402 to the talazoparib group and 403 to the placebo group). Median follow-up for rPFS was 24·9 months (IQR 21·9–30·2) for the talazoparib group and 24·6 months (14·4–30·2) for the placebo group. At the planned primary analysis, median rPFS was not reached (95% CI 27·5 months–not reached) for talazoparib plus enzalutamide and 21·9 months (16·6–25·1) for placebo plus enzalutamide (hazard ratio 0·63; 95% CI 0·51–0·78; p