Abstract 689TiP
Background
Randomized trials have established the combination of long-term ADT and RT as a standard of care treatment paradigm for men with high-risk PC. Nevertheless, approximately 50% of these men will experience biochemical recurrence, and a substantial number will succumb to their disease. Thus, improved therapeutic regimens are needed. Poly ADP-ribose polymerase (PARP) inhibition, which improves survival in men with metastatic castration-resistant PC harboring homologous recombination (HR) defects in comparison to next-generation androgen inhibitors, is one promising strategy for improving outcomes in high-risk localized PC. In preclinical studies, PARP inhibitors have been shown to radiosensitize PC both with and without HR defects, and may also synergize with ADT.
Trial design
This study consists of a phase I lead-in followed by a phase II randomized controlled trial. The phase I component will enroll 27-36 men with non-metastatic Gleason 9-10 PC (PSA≤150ng/mL). All patients will receive ADT for 24 months, dose-escalated intensity-modulated RT (DE-IMRT), and 12 months of niraparib, including 2 months prior to, during, and after DE-IMRT. The dose of niraparib will be escalated from 100mg to 200mg daily during the study, contingent on dose-limiting toxicities, defined as grade 3-4 genitourinary/gastrointestinal toxicity or any grade 4 toxicity lasting > 1 week during the first 6 months of therapy. Once the preferred dose of niraparib is established, 170-180 men with non-metastatic Gleason 9-10 PC, Gleason 8 PC with PSA ≥20 or cT2, or Gleason 7 PC with PSA ≥20 (all with PSA≤150ng/mL) will be enrolled on a phase II randomized controlled trial. Patients will receive ADT for 24 months with DE-IMRT, and will be randomized to treatment with or without niraparib for 12 months. The primary endpoint is the proportion of patients with PSA values < 0.1ng/mL after 24 months of ADT. Exploratory objectives include correlating outcomes with genomic and transcriptomic biomarkers, including HR genes, to identify biomarkers of response to ADT, DE-IMRT, and PARP inhibition.
Clinical trial identification
NRG GU007 (NCT04037254).
Editorial acknowledgement
Legal entity responsible for the study
NRG Oncology.
Funding
“Grants U10CA180868 (NRG Oncology Operations) and U10CA180822 (NRG Oncology SDMC) from the National Cancer Institute (NCI), and Janssen.
Disclosure
Z. Zumsteg: Advisory/Consultancy: EMD Serono; Advisory/Consultancy: Scripps Proton Therapy Center; Spouse/Financial dependant, Wife does legal work for Johnson & Johnson via her law firm King & Spalding: King & Spalding/Johnson and Johnson. M.D. Michaelson: Advisory/Consultancy: Exelixis; Advisory/Consultancy: Eisai; Advisory/Consultancy: Novartis; Advisory/Consultancy: Pfizer. P. Tran: Advisory/Consultancy, Research grant/Funding (self): RefleXion Medical Inc; Advisory/Consultancy: Noxopharm; Advisory/Consultancy: Janssen-Taris Biomedical; Research grant/Funding (self): Astellas Pharmaceuticals; Research grant/Funding (self): Bayer Healthcare. F. Feng: Leadership role, Shareholder/Stockholder/Stock options, Licensing/Royalties: PFS Genomics; Shareholder/Stockholder/Stock options: Nutcracker Therapeutics; Shareholder/Stockholder/Stock options: SerImmune; Honoraria (self): Genentech; Advisory/Consultancy: Bayer; Advisory/Consultancy: Blue Earth Diagnostics; Advisory/Consultancy: Celgene; Advisory/Consultancy: Medivation/Astellas; Advisory/Consultancy: Sanofi Genzyme; Advisory/Consultancy: EMD Serono; Advisory/Consultancy: Janssen Biotech; Research grant/Funding (self): Zenith Epigenetics. All other authors have declared no conflicts of interest.