Testing the Effect of M1774 on Hard-to-Treat Refractory SPOP-mutant Prostate Cancer

PRIMARY OBJECTIVE: I. To evaluate the response rate of the ATR inhibitor tuvusertib (M1774) in highly refractory prostate cancer. SECONDARY OBJECTIVES: I. To evaluate the overall survival (OS) of refractory SPOP-mutant prostate cancer patients receiving M1774. II. To evaluate the progression-free survival (PFS) of refractory SPOP-mutant prostate cancer patients receiving M1774. III. To evaluate the Common Terminology Criteria for Adverse Events (CTCAE) 5.0-defined adverse event (AE) rates of refractory SPOP-mutant prostate cancer patients receiving M1774. EXPLORATORY OBJECTIVE: I. To determine changes in SPOP-mutant circulating tumor deoxyribonucleic acid (ctDNA); SPOP-mutant prostate cancer-derived exosomes, and SPOP-, ATR-, and ATM-related gene signature changes on ATR inhibition, including RAC1, FDFT1, DHCR24, DHCR7, and MVD. OUTLINE: Patients receive tuvusertib orally (PO) every day (QD) on days 1-14 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo biopsy, magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET)/MRI, PET/CT or ultrasound (U/S) and collection of blood samples throughout the trial. After completion of study treatment, patients are followed up every 6 months for 2 years.