1829P - Exposure-safety analyses of talazoparib in combination of enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) in TALAPRO-2 trial

Background

The TALAPRO-2 trial (NCT03395197) showed that the addition of talazoparib (tala), a potent PARP inhibitor, to enzalutamide (enza) significantly improved radiographic progression-free survival in patients with mCRPC. Approximately 75% and 56% of patients (pts) in TALAPRO-2 experienced dose interruption and dose reduction of tala, respectively, due to an adverse event (AE). We investigated the relationship between tala exposure as well as other factors and Grade 3 or higher Anemia, Thrombocytopenia, and Neutropenia, the most common AEs leading to dose interruptions or reductions.

Methods

Safety and PK data from 412 pts in the tala (starting dose of 0.5 mg QD) + enza (160 mg QD) arm were available. To account for the changes in tala exposure over time due to dose modifications and effect of enza and its n-desmethyl metabolite on tala exposure, time-varying average tala concentrations (C_avg,t) were used in the analysis. C_avg,t was calculated as posthoc estimated AUC_t/t based on population PK model. The relationship between C_avg,t/potential predictive factors and the selected safety events was evaluated using Cox proportional hazard (PH) univariate and multivariate models with p value cutoff of 0.05.

Results

Visual examination suggested a higher C_avg,t in pts with Anemia, Thrombocytopenia, and Neutropenia events versus pts without events. Cox PH models indicated that a higher C_avg,t was associated with a higher risk of Grade 3 or higher Anemia, Thrombocytopenia, and Neutropenia. The HR (95% CI) for C_avg,t was 1.433 (1.32, 1.555) for Anemia, 1.609 (1.35, 1.917) for Thrombocytopenia, and 6.942 (3.337, 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 (BWT) and higher baseline lactate dehydrogenase. Higher risk of Neutropenia was associated with lower absolute neutrophil count and lower BWT.

Conclusions

A higher risk of Anemia, Thrombocytopenia, and Neutropenia was associated with higher tala exposure. These findings support the proposed dose modification algorithm as an effective approach for management of AEs.

Clinical trial identification

NCT03395197.

Editorial acknowledgement

Legal entity responsible for the study

Pfizer Inc.

Funding

Pfizer Inc.

Disclosure

A.A. Azad: Financial Interests, Personal, Advisory Board: Astellas, Novartis, Sanofi, AstraZeneca, Tolmar, Telix, Merck Serono, Janssen, BMS, Ipsen, Bayer, Pfizer, Amgen, Noxopharm, Merck Sharpe Dohme; Financial Interests, Personal, Other, Consultant: Aculeus Therapeutics; Financial Interests, Personal, Invited Speaker: Astellas, Janssen, Novartis, Amgen, Ipsen, BMS, Merck Serono, Bayer; Financial Interests, Personal, Other, Travel + Accommodation: Astellas, Merck Serono, Amgen, Novartis, Janssen, Tolmar, Pfizer, Bayer; Financial Interests, Personal, Research Grant: Astellas, Merck Serono, AstraZeneca; Financial Interests, Personal, Steering Committee Member: Astellas, Pfizer, Exelixis; Financial Interests, Institutional, Local PI: BMS, Aptevo Therapeutics, AstraZeneca, GSK, Pfizer, Astellas, SYNthorx, Bionomics, Sanofi, Ipsen, Exelixis, Merck Sharpe Dohme, Janssen, Eli Lilly, Gilead Sciences, Merck Serono, Hinova; Financial Interests, Institutional, Trial Chair: Bayer; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Hinova; Non-Financial Interests, Leadership Role, Chair, Translational Research Committee: ANZUP Cancer Trials Group; Non-Financial Interests, Leadership Role, Member, Scientific Advisory Committee: ANZUP Cancer Trials Group; Non-Financial Interests, Leadership Role, Chair, Urologic Oncology Committee: Clinical Oncology Society of Australia; Non-Financial Interests, Other, Editorial Board Member: BMC Urology; Non-Financial Interests, Other, Associate Editor: Cancer Research Communications, Frontiers in Oncology. Y. Wang, M. Hadigol, J. Hoffman: Financial Interests, Institutional, Stocks/Shares, Employee of Pfizer and may hold Pfizer stock/stock options: Pfizer. N. Agarwal: Financial Interests, Personal, Advisory Board, In the last two calendar years, I participated in the scientific advisory board of these pharma companies between February 2021 to April 2021. None after that: Merck, Aveo, Gilead, Lilly, Exelixis, Foundation Medicine; Financial Interests, Trial Chair, I am involved in the following phase 3 trials as the trial co-chair: TALAPRO-2, TALAPRO-3 (both Pfizer), and CONTACT-2 (Exelxis): Pfizer, Exelixis; Financial Interests, Institutional, Other, I serve in the leadership of my cancer center (Huntsman Cancer Institute, University of Utah. Salt Lake City, UT, USA). There are multiple research projects sponsored by these companies which pay money to my institution: Arnivas, Astellas, AstraZeneca, Bavarian Nordic, Bayer, BMS, Calithera, Celldex, Crispr, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, GSK, Immunomedics, Janssen, Lava, Medivation, Merck, Nektar, Neoleukin, New Link Genetics, Novartis, Oric, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon.; Financial Interests, Steering Committee Member, I am involved in the steering committee of the trials sponsored by these pharmas with no personal honorarium: AstraZeneca, Calithera, Clovis, Crispr, Eisai, Eli Lilly, Exelixis, Immunomedics, Janssen; Financial Interests, Steering Committee Member, I am involved in the steering committee of the trials sponsored by these pharma companies with no personal honorarium: Merck, Nektar, New Link Genetics, Oric, Pfizer, Prometheus, Rexahn, Takeda, and Tracon. N. Matsubara: Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Institutional, Coordinating PI: Janssen, Roche, MSD, Taiho, Pfizer, Chugai; Financial Interests, Institutional, Local PI: AstraZeneca, Bayer, Astellas, Amgen, Eisai, Eli Lilly, AbbVie. V.R. Lincha, F. Zohren, L. DeAnnuntis, D. Wang: Financial Interests, Institutional, Stocks/Shares, Employee of Pfizer and may hold Pfizer stock/stock options: Pfizer.