Abstract 645TiP
Background
TALA is a poly (ADP-ribose) polymerase inhibitor (PARPi) approved as monotherapy for germline BRCA1/2-mutated HER2-negative advanced breast cancer. PARPi have demonstrated substantial clinical efficacy in homologous recombination repair (HRR)/DNA damage response (DDR)-altered metastatic castration-resistant prostate cancers (mCRPC). Phase III study results (de Bono et al. N Engl J Med. 2020;382:2091-2102) led to the approval of olaparib for mCRPC. ENZA is an androgen receptor (AR) inhibitor and established therapy for mCSPC. As PARP activity has been shown to support AR function, PARP inhibition is expected to increase sensitivity to AR-directed therapies. In addition, AR blockade downregulates HRR gene regulation, which has been hypothesized to induce a “BRCAness” phenotype. A Phase II study of TALA monotherapy (TALAPRO-1) demonstrated robust antitumor activity in men with heavily pretreated, HRR-mutated mCRPC. The phase III, double-blind, randomized trial TALAPRO-3 (NCT04821622) herein presented will compare the combination of TALA plus ENZA vs placebo plus ENZA in men with mCSPC with DDR/HRR alterations.
Trial design
Approximately 550 pts with mCSPC harboring DDR/HRR alterations will be randomized to TALA (0.5 mg once daily) plus ENZA (160 mg once daily) or placebo (once daily) plus ENZA (160 mg once daily). Key eligibility criteria are age ≥18 years; histological diagnosis of prostate cancer; alterations in 12 DDR/HRR genes known to sensitize to PARPi (ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C); and metastatic disease (no brain metastases). Primary endpoint is rPFS (time to radiographic progression in soft tissue per RECIST v.1.1 or in bone per PCWG3 criteria by investigator, or death). Secondary endpoints include overall survival, safety, and patient-reported outcomes. Pt recruitment is planned at 285 sites, in 28 countries, including the US, Europe, South America, South Africa, and Asia-Pacific.
Clinical trial identification
NCT04821622.
Editorial acknowledgement
Editorial assistance was provided by Annette Smith, PhD, of CMC AFFINITY, McCann Health Medical Communications, and was funded by Pfizer.
Legal entity responsible for the study
Pfizer.
Funding
Pfizer.
Disclosure
N. Agarwal: Financial Interests, Personal, Other, Consultancy or advisory roles: Astellas Pharma, AstraZeneca, AVEO, Bayer, Bristol-Myers Squibb, Calithera Biosciences, Eisai, EMD Serono, Exelixis, Foundation Medicine, Foundation One Inc., Genentech, Janssen Oncology, Lilly, Medivation/Astellas, MEI Pharma, Merck, Nektar, Novartis, Pf; Financial Interests, Institutional, Funding, Research funding to his institution: Active Biotech, Amgen, AstraZeneca, Bavarian Nordic, Bayer, BN ImmunoTherapeutics, Bristol-Myers Squibb, Calithera Biosciences, Celldex, Eisai, Exelixis, Genentech, GlaxoSmithKline, Immunomedics, Janssen, Merck, Newlink Genetics, Novartis, Pfizer, Prometh. A.A. Azad: Financial Interests, Personal, Other, Honoraria: Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Ipsen, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Noxopharm, Pfizer, Sanofi, Telix, and Tolmar; Financial Interests, Personal, Other, Consulting or Advisory Role: Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Ipsen, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Noxopharm, Pfizer, Sanofi, Telix, and Tolmar; Financial Interests, Personal, Speaker’s Bureau: Amgen, Astellas, Bayer, Bristol-Myers Squibb, Ipsen, Janssen, Merck Serono, and Novartis; Financial Interests, Institutional, Funding, Research Funding: Aptevo Therapeutics (institutional), Astellas (institutional), Astellas (investigator), AstraZeneca (institutional), AstraZeneca (investigator), Bionomics (institutional), Bristol-Myers Squibb (institutional), GlaxoSmithKline (institutional), Ipsen (insti; Financial Interests, Invited Speaker, Travel, accommodation, and expenses: Amgen, Astellas, Janssen, Merck Serono, Novartis, Pfizer, and Tolmar. J. Mateo: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Clovis Oncology, Janssen, Merck/MSD and Roche; Financial Interests, Personal, Speaker’s Bureau: Astellas, AstraZeneca, Guardant Health, Janssen, MSD, and Pfizer; Financial Interests, Institutional, Funding, Received research funding through grants to the institution: AstraZeneca and Pfizer Oncology. N.D. Shore: Financial Interests, Personal, Other, Leadership: Large Urology Group Practice Association; Financial Interests, Invited Speaker, Consulting or Advisory Role: Amgen, AstraZeneca, Bayer, Dendreon, Ferring, Genentech/Roche, Janssen Scientific Affairs, Medivation/Astellas, Myovant Sciences, Pfizer, Sanofi, and Tolmar. J. Chakrabarti: Financial Interests, Personal, Full or part-time Employment, Stocks/Stock options: Pfizer. H. Chen: Financial Interests, Personal, Full or part-time Employment, Stocks/Shares Options: Pfizer. S. Lanzalone: Financial Interests, Personal, Full or part-time Employment, Stocks/Stock options: Pfizer. A. Niyazov: Financial Interests, Personal, Full or part-time Employment, Stocks/Shares: Pfizer. F. Saad: Financial Interests, Personal, Other, Consulting Fees: Astellas Pharma, AstraZeneca/MedImmune, Bayer, Janssen Oncology, and Sanofi; Financial Interests, Institutional, Funding, Funding for research work to his institution: Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Janssen, Pfizer, and Sanofi; Financial Interests, Personal, Other, Honoraria: AbbVie, Amgen, Astellas Pharma, AstraZeneca, Bayer, Janssen Oncology, and Sanofi.