(UroToday.com) The 2023 ESMO annual meeting included a session on prostate cancer, featuring a presentation by Dr. Arun Azad discussing the exposure-safety analyses of talazoparib in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) in the TALAPRO-2 trial. This trial showed that the addition of talazoparib, a potent PARP inhibitor, to enzalutamide significantly improved radiographic progression-free survival in patients with mCRPC (HR 0.63, 95% CI 0.51-0.78).1 However, approximately 75% and 56% of patients in TALAPRO-2 experienced dose interruption and dose reduction of talazoparib, respectively, due to an adverse event. Dr. Azad and colleagues investigated the relationship between talazoparib exposure (as well as other factors) and grade >=3 anemia, thrombocytopenia, and neutropenia, the most common adverse events leading to dose interruptions or reductions.
Safety and pharmacokinetic data from 412 patients (399 patients randomized to receive 0.5 mg of talazoparib; 13 randomized to receive 1 mg talazoparib) in the talazoparib (starting dose of 0.5 mg daily) + enzalutamide (160 mg daily) arm were available. Baseline characteristics of these patients are as follows:
Pharmacokinetic data were analyzed using a population pharmacokinetic (PopPK) approach. For exposure-safety analyses, the time to first incidence of grade >= 3 anemia (hemoglobin < 8.0 g/dL), thrombocytopenia (platelet count <50,000/uL), and neutropenia (absolute neutrophil count <1000/uL were used as safety endpoints. To account for the changes in talazoparib exposure over time due to dose modifications and the effect of enzalutamide and its n-desmethyl metabolite on talazoparib exposure, time-varying average talazoparib concentrations (Cavg,t) were used in the analysis. Cavg,t was calculated as post-hoc estimated AUCt/t based on the population pharmacokinetic model. The relationship between Cavg,t/potential predictive factors, and the selected safety events was evaluated using Cox proportional hazard univariate and multivariate models.
Visual examination suggested a higher Cavg,t in patients with anemia, thrombocytopenia, and neutropenia events versus patients without events:
Cox proportional hazard models indicated that a higher Cavg,t was associated with a higher risk of grade 3 or higher anemia, thrombocytopenia, and neutropenia: HR for Cavg,t was 1.43 (95% CI 1.32, 1.56) for anemia, HR 1.61 (95% CI 1.35, 1.92) for thrombocytopenia, and HR 6.94 (95% CI 3.34, 14.44) for neutropenia. Higher risk of all tested safety endpoints was associated with lower baseline hemoglobin. Higher risk of anemia was associated with lower baseline body weight and higher baseline lactate dehydrogenase. Higher risk of neutropenia was associated with lower absolute neutrophil count and lower baseline body weight. The number of patients who had treatment emergent grade >= 3 anemia, thrombocytopenia, or neutropenia is as follows:
The final model for anemia suggested that an increased risk of grade >= 3 anemia was associated with higher Cavg,t, and baseline lactate dehydrogenase, as well as lower baseline body weight and hemoglobin:
Dr. Azad concluded his presentation by discussing the exposure-safety analyses of talazoparib in combination with enzalutamide in patients with mCRPC in the TALAPRO-2 trial with the following concluding statements:
- A higher risk of anemia, thrombocytopenia, and neutropenia was associated with higher talazoparib exposure
- These findings support the proposed dose modification algorithm as an effective approach for the management of adverse events
Presented by: Arun A. Azad, PhD, MBBS, FRACP, Peter MacCallum Cancer Centre, Melbourne, Australia
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2023 European Society of Medical Oncology (ESMO) Annual Meeting, Madrid, Spain, Fri, Oct 20 – Tues, Oct 24, 2023.
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