No therapies are currently approved for men with mCRPC who have progressed on taxane and NHT. Preclinical evidence has shown that DDR+ prostate tumours may be sensitized to PARP inhibition. TALA inhibits PARP activity and traps PARP on DNA, preventing DNA damage repair and causing cell death in BRCA1/2-mutated cells.
Approximately 100 patients (pts) will be enrolled. Eligible pts are ≥18 yrs with measurable soft tissue disease per RECIST v1.1 and have progressive mCRPC, DDR likely to sensitize to PARP inhibition, ECOG PS ≤ 2, no brain metastases, and received 1-2 CT regimens (including ≥1 taxane-based regimen) and progressed on ≥ 1 NHT (enzalutamide or abiraterone acetate). Pts who received a prior PARP inhibitor, cyclophosphamide, mitoxantrone, or a platinum-based CT within 6 mos of study entry or progressed on a platinum-based CT at any time are excluded. Pts will receive TALA 1 mg/d orally (or 0.75 mg/d for those with moderate renal impairment) until radiographic progression, unacceptable toxicity, or withdrawal of consent. Study drug should not be discontinued based on increased PSA or circulating tumour cell (CTC) count alone. Primary endpoint is best objective response (OR) rate (exact 2-sided 95% CI), defined as a complete or partial soft tissue response per RECIST v1.1. Responses must be confirmed ≥4 wks later by CT/MRI with no evidence of confirmed bone progression per PCWG3 criteria on repeat bone scan ≥6 wks later. Secondary endpoints include time to OR, duration of response, PSA decrease ≥50%, CTC count conversion (to CTC=0 and CTC <5 per 7.5 mL of blood), time to PSA progression, radiographic progression-free survival, overall survival, safety, patient-reported outcomes, and pharmacokinetics of TALA. Efficacy will be assessed every 8 wks during the first 24 wks, then every 12 wks thereafter. An initial safety and efficacy analysis will be performed on 20 pts after receiving study drug ≥8 wks. An interim efficacy analysis is planned when 60 pts have completed ≥6 mos of treatment.
Clinical trial identification
Legal entity responsible for the study
This study was sponsored by Pfizer Inc.
Editorial and medical writing support funded by Pfizer Inc. were provided by Edwin Thrower, PhD, Mary Kacillas and Paula Stuckart of Ashfield Healthcare Communications, Middletown, Connecticut.
J.S. de Bono: Consulting fees: AstraZeneca, Sanofi, Genentech, Astellas, Bayer, Pfizer, Merck Sharp & Dohme, Merck Serono, Boehringer Ingelheim; Honoraria: AstraZeneca, Sanofi, Astellas, Pfizer, Genentech; Contracted research: AstraZeneca, Genentech, Sanofi. C. Higano: Consulting fees: Dendreon, Bayer, Ferring, Orion Corp, Astellas, Clovis, Asana Biosciences, Endocyte, Blue Earth Diagnostics, Myriad Genetics, Tolmar; Honoraria: Genentech; Contracted research Aragon, AstraZeneca, Dendreon, Genentech, Medivation, Emergent BioSolutions, Bayer, Pfizer, Roche, Astellas. F. Saad: Consulting fees: Astellas, Janssen, Amgen, Sanofi, AstraZeneca; Honoraria: Astellas, Abbvie, Amgen, Janssen, Sanofi, Bayer; Contracted research: Astellas, Bayer, Amgen, Janssen, BMS, Oncogenex, Sanofi. K. Miller: Consulting fees, Honoraria: Advanced Accelerator Applications, Amgen, Bayer, BMS, Ferring, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sotio, Tolmar. M. Casey, A. Czibere, C. Healy: Employee: Pfizer, Inc. K. Fizazi: Consulting fees, honoraria: Astellas.