San Francisco, CA (UroToday.com) Multiple clinical trials are investigating the efficacy of PARP inhibitors in men with metastatic castration-resistant prostate cancer (mCRPC) with somatic and/or germline (DNA damage repair) DDR alterations. Talazoparib is a PARP inhibitor that both inhibits and traps the PARP enzyme with in vitro studies demonstrating that talazoparib has greater PARP-trapping activity than other PARP inhibitors. Talazoparib is FDA approved for women with breast cancer with a germline BRCA1/2 mutation.
TALAPRO-1 is an international Phase II study (NCT03148795) evaluating talazoparib in men with mCRPC and DDR alterations. Eligible men have measurable soft tissue disease, and a mono-allelic or bi-allelic DDR alteration in one of the following genes: ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C. In this study, the investigators reported results of a planned interim efficacy (primary endpoint: best overall soft tissue response rate by RECIST criteria) and safety analysis. At the time of analysis 81 men were treated with talazoparib 1 mg daily. Of these patients 58% had discontinued treatment; median duration of treatment was 16 weeks. 43 patients had received treatment for at least 16 weeks and were eligible for evaluation of the primary endpoint; all had received prior docetaxel and half had received prior cabazitaxel. The following DDR alterations were present in the primary endpoint cohort: 41.9% BRCA2, 32.6% ATM, 4.7% BRCA1, 4.7% PALB2, and 16.3% other.
In the efficacy analysis, the objective response rate was 25.6% in the overall cohort and 50% in patients with BRCA1/2 alterations. 4.7% of patients had a complete response, all of whom had alterations in BRCA1/2. Only 7.1% of patients with ATM alterations had an objective response. PSA decline of 50% or greater from baseline was observed in 34% of the overall cohort. Again, these responses were enriched in patients with BRCA1/2 alterations (64%), as well as PALB2 alterations (33%). Only 1 of 15 patients (7%) with ATM alterations had a PSA response and 0 of 10 patients with other DDR alterations.
Radiographic progression-free survival (rPFS) was 5.6 month in the overall cohort. Categorized by DDR alteration, median rPFS was longer in patients with BRCA1/2 alterations (8.2 months; 95% confidence interval 5.6 to not evaluable) compared with patients with other alterations (range 3.2 to 4.7 months).
Of 81 patients evaluable in the safety analysis, rates of any treatment-emergent adverse event (TEAE) and Grade 3 or 4 TEAE were 93.8% and 49.4%, respectively. 79.0% of patients experienced a study-drug-related TEAE and 40.7% experienced a Grade 3 or 4 study-drug-related TEAE. 4.9% of patients experienced a Grade 5 TEAE, none of which were related to the study drug. The most common TEAEs (occurring in greater than 10% of patients) and adverse drug reactions (study-drug-related TEAEs) are outlined in the figure below.
The authors concluded with the following take-home points:
- In this interim analysis of TALAPRO-1, talazoparib monotherapy demonstrated anti-tumor activity in mCRPC patients with DDR alteration who have previously received taxane chemotherapy and next-generation hormonal therapy with a conformed overall response rate of 25.6%
- Efficacy was most notable in the subset of patients with mCRPC whose tumor harbored BRCA1/2 alterations with a confirmed objective response rate of 50%
- In this patient population, talazoparib monotherapy was generally well-tolerated
- Anemia was the most frequent TEAE reported and was managed by dose modifications
- No new safety signals were observed in this patient population compared with the known safety profile of talazoparib
Presented by: Johann De Bono, MD, PhD, Regius Professor of Cancer Research and Professor in Experimental Cancer Medicine at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust
Written by: Jacob Berchuck, MD, Medical Oncology Fellow at the Dana-Farber Cancer Institute (Twitter: @jberchuck) at the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California