Trevor A. Graham

Adaptive Therapy Exploits Fitness Deficits in Chemotherapy-Resistant Ovarian Cancer to Achieve Long-Term Tumor Control

Abstract Drug resistance results in poor outcomes for patients with cancer. Adaptive therapy is a potential strategy to address drug resistance that exploits competitive interactions between sensitive and resistant subclones. In this study, we showed that adapting carboplatin dose according to tumor response (adaptive therapy) significantly prolonged survival of murine ovarian cancer models compared with standard carboplatin dosing, without increasing mean daily drug dose or toxicity. Platinum-resistant ovarian cancer cells exhibited diminished fitness when drug was absent in vitro and in vivo, which caused selective decline of resistant populations due to reduced proliferation and increased apoptosis. Conversely, fitter, sensitive cells regrew when drug was withdrawn. Using a bioinformatics pipeline that exploits copy number changes to quantify the emergence of treatment resistance, analysis of cell-free DNA obtained longitudinally from patients with ovarian cancer during treatment showed subclonal selection through therapy, and measurements of resistant population growth correlated strongly with disease burden. These preclinical findings pave the way for future clinical testing of personalized adaptive therapy regimens tailored to the evolution of carboplatin resistance in individual patients with ovarian cancer. Significance: Carboplatin adaptive therapy improves treatment efficacy without increasing daily dose due to reduced fitness of drug-resistant populations, which can be tracked using cfDNA and could direct adaptive therapy in future clinical trials. See related commentary by Gatenby, p. 3373

Study protocol for Adaptive ChemoTherapy for Ovarian cancer (ACTOv): a multicentre phase II randomised controlled trial to evaluate the efficacy of adaptive therapy (AT) with carboplatin, based on changes in CA125, in patients with relapsed platinum-sensitive high-grade serous or high-grade endometrioid ovarian cancer

Introduction Adaptive ChemoTherapy for Ovarian cancer (ACTOv) is a phase II, multicentre, randomised controlled trial, evaluating an adaptive therapy (AT) regimen with carboplatin in women with relapsed, platinum-sensitive high-grade serous or high-grade endometrioid cancer of the ovary, fallopian tube and peritoneum whose disease has progressed at least 6 months after day 1 of the last cycle of platinum-based chemotherapy. AT is a novel, evolutionarily informed approach to cancer treatment, which aims to exploit intratumoral competition between drug-sensitive and drug-resistant tumour subpopulations by modulating drug dose according to a patient’s own response to the last round of treatment. ACTOv is the first clinical trial of AT in this disease setting. Methods and analysis 80 patients will be randomised 1:1 to standard therapy (control) or AT (investigational) arms. The starting and maximum carboplatin dose in both arms is area under the curve (AUC) ×5 according to absolute nuclear medicine glomerular filtration rate. The AT regimen will modify the carboplatin dose according to changes in the serum biomarker CA125, a proxy measure of total tumour burden. Patients will receive treatment intravenously every 21 days for a maximum of 6 and 12 cycles in the control and investigational arms, respectively. The primary endpoint is modified progression-free survival (investigator-assessed using RECIST 1.1 (Response Evaluation Criteria in Solid Cancers) compared with the baseline prerandomisation scan rather than the radiological nadir), clinical progression or death from any cause. Secondary endpoints will include acceptability, deliverability, compliance, toxicity, CA125, quality of life and overall survival. ACTOv is open to National Health Service hospitals throughout the UK, recruitment is anticipated to take 36 months across 10 sites and will be managed by the Cancer Research UK and University College London Cancer Trials Centre. Ethics and dissemination The trial has been reviewed and received approval from the London—Dulwich Research Ethics Committee (REC). Results of the trial will be disseminated through publication in peer-reviewed journals. Trial registration number NCT05080556 .