The purpose of this study is to find out whether mevrometostat in combination with enzalutamide delays cancer progression in people with metastatic castration-resistant prostate cancer (mCRPC) who have previously received enzalutamide, darolutamide, or apalutamide in the metastatic castration-sensitive prostate cancer (mCSPC) or non-metastatic castration-resistant prostate cancer (nmCRPC) setting but have not previously progressed on abiraterone.

Inclusion Criteria:

• Willing and able to provide written informed consent
• Age 18 years or older
• Diagnosis of prostate cancer (adenocarcinoma) confirmed by tissue sample, without neuroendocrine or small cell features
• Currently taking or recently treated with enzalutamide, darolutamide, or apalutamide (within 30 days of screening) and willing to switch to or restart enzalutamide for this study
• Cancer has spread to bone or soft tissue (metastatic disease), confirmed by imaging
• ECOG performance status of 0, 1, or 2 (able to care for self and up and about more than 50% of waking hours)
• Testosterone level less than 50 ng/dL at screening, with ongoing hormone deprivation therapy or prior surgical castration
• If receiving bone-protective therapy (e.g., denosumab or bisphosphonates), must be on a stable dose for at least 4 weeks
• Evidence of cancer progression while on enzalutamide, darolutamide, or apalutamide, shown by rising PSA, worsening disease on imaging, or new bone lesions
• Adequate organ function based on blood tests within 28 days of starting treatment, including adequate blood counts, kidney function, and liver function
• Willing to use acceptable birth control during the study and for 30 days after the last dose

Exclusion Criteria:

• History of myelodysplastic syndrome, acute myeloid leukemia, or other prior cancer (exceptions: non-melanoma skin cancer, carcinoma in situ, cancers more than 3 years ago with no recurrence, or early-stage cancers with low risk of recurrence)
• Any medical or psychiatric condition, including active infection or recent suicidal ideation, that may make study participation unsafe
• History of seizure or conditions that may increase seizure risk (e.g., prior stroke, significant brain trauma), or loss of consciousness or transient ischemic attack within 12 months
• Untreated brain metastases, spinal cord compression, or clinically significant epidural disease
• Use of 5-alpha reductase inhibitors, herbal medications, or supplements known to alter PSA levels within 4 weeks of starting treatment
• AIDS-related illness or active hepatitis B or C (well-controlled HIV is allowed)
• Known history of chronic liver disease (e.g., alcoholic liver disease, primary biliary cirrhosis, autoimmune hepatitis, Wilson's disease, hemochromatosis)
• Known history of active inflammatory gastrointestinal disease, chronic diarrhea, or prior gastric resection or lap-band surgery
• Clinically significant cardiovascular disease within the past 6 months (e.g., heart attack, unstable angina, stroke, heart failure NYHA Class III/IV, pulmonary embolism, significant arrhythmias), cardiac pacemaker, or QTcF greater than 480 msec on screening ECG
• Prior or current use of PARP inhibitors and/or AKT inhibitors
• Prior cancer progression on abiraterone (stopping abiraterone due to side effects is allowed)
• Known allergy to any study drug
• Blood transfusion within 28 days prior to screening blood tests
• Use of another investigational drug within 4 weeks before starting study treatment
• Any other condition that, in the opinion of the investigator, would prevent safe participation
• Current use or anticipated need for strong CYP3A4/5 inhibitors or inducers (other than enzalutamide) within 10 days or 5 half-lives prior to treatment start

The Prostate Cancer Clinical Trials Consortium, LLC supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: pcctc@mskcc.org.