NRG-GY036: A phase III trial of one vs. two years of maintenance olaparib, with or without bevacizumab, in patients with <i>BRCA1/2</i> -mutated or homologous recombination deficient (HRD+) ovarian cancer following response to first line platinum-based chemotherapy.

Abstract

TPS5634 Background: The profound progression-free survival (PFS) benefit shown in the SOLO-1 and PAOLA-1 randomized clinical trials set the standard of 2 years of PARP inhibitor (PARPi) maintenance with olaparib, with or without bevacizumab, in patients with BRCA1/2 -mutated and homologous recombination deficient (HRD+) ovarian carcinoma after response to frontline platinum-based chemotherapy, and this was approved by the FDA in December 2018. However, newer studies have elucidated the long-term toxicity risk of prolonged PARPi use, specifically treatment-related myeloid neoplasms (TMN), along with detrimental effects on subsequent platinum-based chemotherapy and overall survival. Given this, we seek to test de-escalation of PARPi maintenance therapy, evaluating if 1 year is non-inferior to 2 years, using a pragmatic and streamlined study design. Methods: NRG GY036 is a phase III, randomized, non-inferiority study of 1 versus 2 years of olaparib maintenance, with our without bevacizumab, in those with BRCA1/2 -associated and HRD+ ovarian cancer, after response to frontline platinum-based chemotherapy (NCT06580314). Key eligibility criteria include a deleterious BRCA1/2 mutation, germline or somatic, or HRD+ tumor using any CLIA-certified test. Patients must have undergone cytoreductive surgery and had a clinical response after a minimum of 4 cycles of platinum-based chemotherapy. The primary endpoint is investigator assessed PFS using RECIST v1.1 criteria for 1 vs. 2 years in a modified intention to treat (mITT) population, where time at risk starts 360 days after randomization to account for the time where both arms receive the same treatment. Secondary endpoints include overall survival (OS), PFS2, PFS in the ITT and as-treated populations, and toxicity including rates of TMN. The statistical design is based on a hazard ratio non-inferiority margin of 1.36 (1-sided alpha 0.05, power 0.9). The null hypothesis will be rejected if HR &lt;1.15, giving 90% certainty that the true median PFS loss is not more than 10 months based on historical controls from SOLO1 and the HRD+ subgroup of PAOLA-1. We anticipate enrolling 880 patients to have at least 735 patients in the mITT population. This IND-exempt study pragmatically mimics real-world clinical practice by using commercially available drug, implementing broad eligibility criteria, allowing physician’s choice bevacizumab, and incorporating individual physician and institution’s standard practices. It also employs a streamlined approach with minimal data collection forms and abbreviated adverse event reporting. NRG GY036 was activated on 1/16/2025. The first patient enrolled on 3/12/2025. As of 1/16/2026, there are 676 participating sites and 152/880 (17%) patients enrolled. Clinical trial information: NCT06580314 .