Talazoparib (TALA), an oral poly (ADP-ribose) polymerase (PARP) inhibitor for men with metastatic castration-resistant prostate cancer (mCRPC) and DNA damage response (DDR) alterations: Detailed safety analyses from TALAPRO-1 trial.
Authors: Mehra Niven , Fizazi Karim , De Bono Johann S. , Barthélémy Philippe , Dorff Tanya B. , Stirling Adam Patrick , Machiels Jean-Pascal H. , Bimbatti Davide , Kilari Deepak , Dumez Herlinde , Buttigliero Consuelo , van Oort Inge M. , Castro Elena , Chen Hsiang-Chun , Di Santo Nicola , DeAnnuntis Liza L , Healy Cynthia G. , Scagliotti Giorgio V. 
Published: June 2021

5047 Background: PARP inhibitors have recently been approved for the treatment of mCRPC. In this Phase 2 study, we explore the safety profile of TALA in men with mCRPC with the aim of understanding how patients (pts) with adverse events (AEs) were managed during the trial. Methods: TALAPRO-1 (NCT03148795) is a single-arm, open-label, phase 2 study of TALA in pts with progressive mCRPC, measurable soft tissue disease, and DDRm likely to sensitize to PARPi ( ATM, ATR, BRCA1/2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), who received ≥1 taxane-based chemotherapy and progressed on ≥1 novel hormonal therapy (enzalutamide/abiraterone). The primary objective was confirmed objective response by central independent review; the assessment of safety included AEs, incidence of dose modifications and of permanent treatment discontinuation due to AEs, and clinical laboratory tests. Results: In the TALA-treated population (1 mg/daily; n=127), 95.3% (121/127) experienced all-causality AEs. The most common (≥15%) hematologic AEs were anemia (any grade, 48.8%; G3, 30.7% [no G4 events]), thrombocytopenia (all grade, 18.9%; G3/4, 8.7%), and neutropenia (all grade, 16.5%, G3, 7.9% [no G4]). Median time from first dose of TALA to onset of first episode of G≥3 anemia, neutropenia, and thrombocytopenia was 56, 48, and 17 days, respectively. G3 anemia lasted a median of 7 days, G3 neutropenia lasted a median of 12 days, G3 and G4 thrombocytopenia lasted a median of 8 and 11 days, respectively. Hematologic AEs typically occurred during the first 4–5 months of TALA treatment and were managed by dose modifications and supportive care. 34.6% of pts received a blood transfusion product, and most transfusions occurred when hemoglobin was between 7.0–10.0 g/dL. Overlapping G3/4 hematologic AEs were infrequent on TALA (anemia + neutropenia 4.7%; anemia + thrombocytopenia 5.5%; neutropenia + thrombocytopenia 1.6%). In pts who had anemia, 12.6% also had fatigue; in those with thrombocytopenia, 4.7% had a subsequent bleeding event; in those with neutropenia, 1.6% had an overlapping infection. The most common non-hematologic AEs (≥15%) were nausea (any grade, 33.1%; G3/4, 2.4%), decreased appetite (any grade, 28.3%; G3/4, 3.1%), and asthenia/fatigue (any grade, 23.6%/19.7%; G3/4, 3.9%/1.6%). In the treated population, dose reduction of TALA due to all-causality AE occurred in 33 pts (26.0%). Treatment discontinuation due to all-causality AEs was low and occurred in 15 pts (11.8%); the most frequent (≥2 pts) AEs leading to discontinuation of TALA were back pain and platelet count decrease (each, 1.6% [2/127 pts]). There were no treatment-related deaths. Conclusions: A manageable safety profile and durable antitumor effects were observed with TALA in men with heavily pretreated mCRPC in this phase 2 study. Clinical trial information: NCT03148795.