Window study of the PARP inhibitor rucaparib in patients with primary triple negative or BRCA1/2 related breast cancer (RIO)

Triple negative breast cancer (TNBC) constitutes 10-15% of breast cancers and currently no effective targeted treatments exist to improve outcome. PARP inhibitors are effective in germline BRCA (gBRCA) mutated breast cancer due to homologous recombination deficiency, a pathway known to be impaired in TNBC. It is hypothesised that defects in homologous recombination within sporadic TNBC subgroups could enhance responsiveness to PARP inhibition. However, trials have failed to show favourable responses with PARP inhibitors in heavily pre-treated advanced TNBC. RIO aims to determine the proportion of sporadic TNBCs that display sensitivity to the PARP inhibitor rucaparib and establish biomarkers that distinguish this subgroup, enabling identification of patients likely to benefit from rucaparib treatment. Trial design: RIO is a single-group, open-label, phase II window of opportunity study assessing rucaparib efficacy in patients prior to commencing primary treatment. 81 primary, sporadic TNBC and up to 20 known gBRCA mutated patients will be recruited. Patients receive 12-14 days of rucaparib with core biopsies and research bloods collected pre- and post-treatment. Follow-up is 28 days post end of trial treatment (EoTT). Baseline biopsies are collected at time of diagnostic biopsy or following trial entry. EoTT biopsies are taken during surgery or prior to neo-adjuvant chemotherapy. The primary endpoint is Ki67 response from baseline to end of rucaparib treatment in sporadic TNBC. Response is defined as ≥ 50% fall in Ki67 from baseline. Secondary and exploratory endpoints aim to define biomarkers associated with rucaparib responsiveness and surrogate markers of efficacy. The first patient was enrolled in August 2015. The trial is being conducted in the UK with 12-14 participating centres anticipated. The study is open to new centres with recruitment expected to complete early 2017. The RIO trial will allow biological effects of rucaparib in a treatment naïve TNBC population to be assessed, enhancing biological understanding of TNBC subgroups. If successful, the results will inform future studies in targeted treatment options available for TNBC patients. Clinical trial identification: ISRCTN 92154110 CRUK/12/034 Legal entity responsible for the study: The Institute of Cancer Research: Royal Cancer Hospital (ICR) and The Royal Marsden NHS Foundation Trust Clovis Oncology Inc. This study has been endorsed by Cancer Research UK (CRUK/12/034)