1834P - Exposure-efficacy analyses of talazoparib in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) in the 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 (rPFS) in mCRPC unselected for DNA damage repair deficiencies. The objective of the analysis was to evaluate the relationship between TALA exposure and rPFS to support the recommended TALA dosing regimen in combination with ENZA and identify potential prognostic factors for rPFS

Methods

Efficacy and pharmacokinetics (PK) data from 391 patients in Part 2 Cohort 1 (All-comers group) who received TALA starting dose of 0.5 mg QD plus 160 mg QD ENZA were included in the analyses. 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 over time, time-varying average TALA concentrations (C_avg,t) were used in the analysis. C_avg,t was calculated as post-hoc estimate AUC_t/t based on population PK model. The relationship between C_avg,t as well as potential prognostic factors and rPFS was evaluated using Cox proportional hazard univariate and multivariate models with p value cutoff of 0.05.

Results

Visual examination suggested higher C_avg,_t in patients with longer rPFS than in those with shorter rPFS. Multivariate analysis showed that higher exposure was associated with longer rPFS. Lower baseline lactate dehydrogenase, lower baseline alkaline phosphatase, absence of measurable disease and bone only metastatic disease were associated with longer rPFS, while lower baseline lymphocyte was associated with shorter rPFS.

Conclusions

Longer rPFS was found to be associated with higher C_avg,t, This supports using 0.5 mg QD (in combination with ENZA) which provides similar exposure as 1 mg QD, the maximum tolerable dose of TALA monotherapy, for the treatment of mCRPC. These data also support treating grade 1-2 AEs with symptomatic management without TALA dose reduction to maximize efficacy.

Clinical trial identification

NCT03395197.

Editorial acknowledgement

Third party editorial assistance was not used for the abstract.

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. V.R. Lincha, M. Hadigol, J. Hoffman, Y. Wang, L. DeAnnuntis, F. Zohren, D. Wang: Financial Interests, Institutional, Stocks/Shares: Pfizer, Inc. 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.