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

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.

Niraparib for the treatment of metastatic ccRCC in a patient with CDK12 and RAD51C mutations: a case report

“…At the same time, recent studies propose that the effectiveness of PARPi is not solely dependent on BRCA deficiency but may also be affected by mutations in other genes within HRR pathway ( Boussios et al, 2020 ). In a clinical trial of prostate cancer focusing on alterations in the HRR genes, including BRCA1 , BRCA2 , PALB2 , ATM , ATR , CHEK2 , FANCA , RAD51C , NBN , MLH1 , MRE11A , and CDK12 , the group treated with talazoparib showed a significant improvement in progression-free survival compared to the placebo group ( Fizazi et al, 2023 ). Soon afterwards, the FDA granted further approval for the application of talazoparib in the treatment of prostate cancer patients exhibiting mutations in HRR pathway genes, encompassing CDK12 and RAD51C ( Akbıyık and Ürün, 2023 ).…”

PARP Inhibitors in Metastatic Castration-Resistant Prostate Cancer: Unraveling the Therapeutic Landscape

“…The most common HRR mutation found in these patients was BRCA2 (34%), followed by ATM (22%), CDK12 (19%), and CHEK2 (18%). Germline mutation testing was positive in 91 out of 302 evaluable patients (30.1%) enrolled in the study [26]. Recent data showed that rPFS was significantly longer in patients with HRRm treated with talazoparib plus enzalutamide compared to those receiving placebo plus enzalutamide (median not reached vs. 13.8 months, HR 0.45, 95% CI 0.33-0.61, p < 0.0001).…”

“…The rPFS improvement reached 80% in patients with BRCA1/2 alterations (HR 0.20, 95% CI 0.11-0.36, p < 0.0001). Although OS data remain immature, analysis at data cutoff favored the talazoparib group (HR 0.69, 95% CI 0.46-1.03, p = 0.07) [26].…”

“…** Inverse probability censoring weighting analysis of overall survival, a prespecified analysis of overall survival, adjusted for the imbalance between the two treatment groups receiving subsequent PARP inhibitors and other life-prolonging therapies [25]. + Based on the results of the HRR-deficient cohort of the TALAPRO-2 trial [26]. Abbreviations: AE, adverse event; ARPI, androgen receptor pathway inhibitor; bid, twice daily; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; HRRm, homologous recombination repair gene mutated; IQR, inter-quartile range; mCRPC, metastatic castration-resistant prostate cancer; mCSPC, metastatic castration-sensitive prostate cancer; NA, not available; nmPC, non-metastatic prostate cancer; NR, not reached; ORR, objective response rate; OS, overall survival; PSA, prostate-specific antigen; qd, once daily; rPFS, radiographic progression-free survival; TEAEs, treatment-emergent adverse events.…”

Androgen receptor, PARP signaling, and tumor microenvironment: the ‘perfect triad’ in prostate cancer?

“…Discontinuation rates did not change significantly between the two groups; however, the median time to QoL deterioration was significantly higher in the combined treatment group compared to the PBO plus Enzalutamide group (38.0 versus 25.0 months, HR, 0.78; 95% CI, 0.62 to −0.99; p = 0.04). 67 , 68 …”