Combining standard therapy with sintilimab improves outcomes in locoregionally-advanced nasopharyngeal carcinoma patients

The phase III TALAPRO-2 study is the first of its kind to investigate the efficacy of the combination of talazoparib plus enzalutamide as a first-line treatment in men with metastatic castration-resistant prostate cancer. This study supports the benefit of the combination of talazoparib plus enzalutamide over a current standard of care, enzalutamide alone, on radiographic progression-free survival. Treatment with the combination treatment also resulted in a delay in the time to clinically meaningful deterioration in quality of life. No new safety concerns were identified and toxicity was generally manageable and in line with known safety profiles.

One current standard of care for the treatment of metastatic castration-resistant prostate cancer (mCRPC) involves the use of enzalutamide, an androgen receptor inhibitor. mCRPC remains an area with a large unmet need for novel therapies. Given the ever-evolving technologies in the treatment of cancer, research aiming to improve current therapies is continually being carried out. This study builds on the previous TALAPRO-1 study which reported the durable anti-tumour activity and manageable safety of talazoparib monotherapy (1 mg/day) in patients with heavily pretreated mCRPC with homologous recombination repair (HRR) gene alterations. The phase III TALAPRO-2 study aimed to investigate the combined efficacy of talazoparib (0.5 mg/day) plus enzalutamide (160 mg/day) as a first-line treatment in men with mCRPC. At ASCO 2023, the results of cohort 2 of this study were presented.

Study design

TALAPRO-2 is a multinational phase III, two-part trial among men with first line mCRPC with an ECOG performance status 0 or 1, with or without DNA damage response (DDR) alterations. Enrolled patients may not have undergone any systemic treatment with the exception of androgen-deprivation therapy or anti-androgens. This study was split into 2 cohorts; cohort 1 (open-label, non-randomised study) involved 636 patients who were non-deficient or with unknown DDR alterations (treatment; N= 402, placebo; N= 403) and patients with HRR mutations (N= 169) patients; cohort 2 (randomised, double-blind, placebo-controlled study) involved 399 patients with HRR mutations (treatment; N= 200, placebo; N= 199). The patients in cohort 2 were randomised 1:1 to receive either a combination of talazoparib (0.5 mg/day) plus enzalutamide (160 mg/day) or placebo plus enzalutamide. Of note in this population, 37.5% of men receiving the treatment combination had received abiraterone or docetaxel previously for mCRPC. The primary endpoint of the trial was radiographic progression-free survival (rPFS).

Results

Treatment with talazoparib plus enzalutamide significantly reduced the probability of rPFS, with a 55% reduction in risk of progression or death. In the placebo arm, the median time to rPFS was 13.8 months, and this endpoint was not reached in the combination treatment arm. Of note, patients who had previously received abiraterone or docetaxel displayed the same benefits in terms of rPFS as those who had not (HR[95%CI]: 0.43[0.26-0.7] vs. 0.46[0.31-0.69] respectively). Patients with HRR alterations that involved BRCA displayed an 80% reduction in the risk of progression or death, whereas those with non-BRCA alterations derived a more modest benefit of this combination treatment (HR[95%CI]:  0.2[0.11-0.36] vs. 0.68[0.46-1.02]. Overall survival data are immature (24% maturity), however, 21.5% of patients receiving the combination treatment and 26.6% receiving placebo had died, with a median of 33.7 months in the placebo arm and not yet reached in the combination treatment arm (HR[95%CI]: 0.69 [0.46-1.03]. Data on the secondary endpoint, time to prostate-specific antigen (PSA) progression, also revealed a benefit of the combination treatment over placebo with a median time to progression of 28.6 vs. 11.1 months (HR[95%CI]: 0.41[0.3-0.57]). Objective response rates in the combination treatment group were 67.1% vs. 40% in the placebo group. While there was a higher occurrence of grade 3-4 adverse events in the combination treatment arm (66.2% vs. 37.2% in the placebo group), and a higher incidence of dose interruption or reduction due to an adverse event (interruption; 67.2% vs. 19.6%; reduction 55.6% vs. 6%), no cases of myelodysplastic syndrome or acute myeloid leukaemia were identified. The most common adverse event reported was anaemia (64.6% vs. 15.6% all grades, 42.9% vs. 4.5% grade 3-4), however 55.6% of patients presented with grade 1-2 anaemia at baseline.

Conclusion

Treatment with talazoparib plus enzalutamide led to a clinically meaningful and statistically significant improvement in the primary endpoint rPFS versus placebo plus enzalutamide. No new safety signals were identified, and the time to clinically meaningful decrease in quality of life was prolonged in the combination treatment group. Thus, this combination treatment possesses the potential to become a first-line treatment for patients with mCRPC and HRR gene alterations.

Reference

Fizazi K, et al. TALAPRO-2: Phase 3 study of talazoparib plus enzalutamide versus placebo plus enzalutamide as first-line treatment for patients with metastatic castration-resistant prostate cancer harboring homologous recombination repair gene alterations. Presented at ASCO 2023; Abstract 5004.