Impact of rucaparib on circadian rhythms and adverse events in ovarian cancer: Insights from the MAMOC trial.

Abstract

5578 Background: Ovarian cancer (OC) is a leading cause of gynaecologic cancer mortality, with most cases diagnosed at an advanced stage. Standard treatment involves cytoreductive surgery followed by chemotherapy. In high-grade OC, maintenance therapy, including PARP inhibitors (PARPi), plays a crucial role in delaying disease progression. PARP1, the primary target of these agents, interacts with the CLOCK-BMAL1 complex, which regulates circadian rhythms. This study investigates circadian disturbances in BRCA wild-type OC patients receiving rucaparib compared to placebo and evaluates their impact on patient-reported outcomes. Methods: This study is part of the Phase III, randomized, double-blind, placebo-controlled MAMOC trial (NCT04227522), which enrolled 42 patients with advanced high-grade OC after platinum-based chemotherapy and bevacizumab maintenance. Rucaparib was given to 28 patients, while 14 received placebo. Daily activity data and patient-reported outcomes, including quality of life (EORTC-QLQ-C30/OV28), Fatigue Symptom Inventory (FSI), and adverse event (AE/SAE) data, were collected for all patients. A subset of 15 patients (5 placebo, 10 rucaparib) underwent molecular circadian clock analysis using saliva samples collected pre-, during, and post-treatment to assess changes in the clock and cancer-related pathways via qPCR and NanoString technology. Mathematical modelling was used to determine 24-hour toxicity profiles. Results: Rucaparib treatment caused significant disruptions in circadian gene expression, notably a reduction in BMAL1 expression, followed by an increase in BMAL1 and PER2 levels post-treatment. Dysregulation of BMAL1 and PER2 correlated with the frequency and severity of side effects, including fatigue. Circadian parameters such as amplitude, MESOR, and phase were predictive of patient-reported outcomes. In the rucaparib group, circadian parameters exhibited opposing associations with outcomes compared to placebo. Clock-associated genes, including NFIL3 and GSK3B , showed altered expression patterns that normalized after treatment. Additionally, rucaparib induced phase shifts and amplitude changes in clock and cancer-related genes like CRY2 , RORC , and TP53 , which were associated with increased adverse effects, particularly fatigue and nausea. Mathematical modelling revealed variability in toxicity profiles based on individual circadian rhythms pointing to the relationship between clock disruption and side effect severity. Conclusions: Our findings highlight the role of circadian rhythm dysregulation in the toxicity of PARPi in OC. The study suggests that chronotherapy, aligning drug administration with patients circadian rhythms, may reduce side effects. Incorporating circadian biology into treatment strategies could thus contribute to optimize cancer therapies by enhancing efficacy while minimizing toxicity. Clinical trial information: NCT04227522 .