Integrating mathematical modelling and wet-lab experiments to examine the scope for adaptive treatment scheduling of PARP inhibitors in ovarian cancer

Abstract PARP inhibitors (PARPis) represent a great advancement in the treatment of ovarian cancer, yet these drugs often fail after a few months due to emerging drug resistance. A recent clinical trial in prostate cancer showed that evolutionary-inspired, adaptive drug scheduling significantly delayed time to progression. This approach adaptively skipped treatment to maintain a pool of drug-sensitive cells that suppressed resistant cells through competition. Here, we present results from a combined modelling and experimental study in which we investigated whether adaptive therapy could delay resistance to the PARPi olaparib in ovarian cancer.We performed a series of in vitro experiments in which we used Incucyte Zoom time-lapse microscopy to characterize the cell population dynamics under different PARPi schedules. Leveraging these data we developed an ordinary differential equation mathematical model of treatment response, and used this model to test different plausible adaptive treatment schedules. Our model can accurately predict the in vitro treatment dynamics, even to new schedules, and suggests that treatment modifications need to be carefully timed, or one risks losing control over tumor growth, even in the absence of any resistance. This is because multiple rounds of cell division are required for cells to acquire sufficient DNA damage to induce apoptosis. As a result, adaptive therapy algorithms that modulate treatment but never completely withdraw it are predicted to perform better in this setting than strategies based on treatment interruptions. Subsequent experiments confirm this prediction in vivo. To conclude, we present preliminary work aiming at investigating the scope for clinical translation of our results by confronting our model with longitudinal CA-125 data from 53 ovarian cancer patients receiving olaparib at Moffitt. Overall, this study contributes to a better understanding of the impact of scheduling on treatment outcome for PARPis, and showcases some of challenges involved in developing adaptive therapies for new treatment settings. Citation Format: Maximilian Strobl, Mehdi Damaghi, Alexandra Martin, Samantha Byrne, Mark Robertson-Tessi, Robert Gatenby, Robert Wenham, Philip Maini, Alexander R.A. Anderson. Integrating mathematical modelling and wet-lab experiments to examine the scope for adaptive treatment scheduling of PARP inhibitors in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr B009.