A Phase 1, Multicenter Trial Evaluating the Safety, Tolerability, and Efficacy of Valemetostat (DS-3201) in Combination With Darolutamide in Metastatic Castration Resistant Prostate Cancer (mCRPC)

Key Inclusion Criteria: The clinical site will screen for the full inclusion criteria per protocol. 1. Adult males ≥18 years of age at the time the ICF is signed (Please follow local regulatory requirements if the legal age of consent for trial participation is \>18 years old). 2. Histologically confirmed adenocarcinoma of the prostate. Cases exhibiting neuroendocrine differentiation are eligible for enrollment, except those with a diagnosis of pure small cell carcinoma, which is excluded. 3. Evidence of disease progression as per the PCWG3 modified RECIST v1.1 criteria. 4. Evidence of metastatic disease as confirmed by radiographic imaging (CT, MRI, or bone scan). 5. Ongoing androgen deprivation at time of enrollment. • For participants currently being treated with luteinizing hormone-releasing hormone agonists or antagonists, therapy must have been initiated at least 4 weeks prior to enrollment and treatment must be continued throughout the trial. 6. Baseline PSA expression level of ≥2 ng/mL, according to a documented testing result. 7. Prior therapy with an Androgen Receptor Pathway Inhibitors (ARPI). 8. ECOG PS of 0 or 1 assessed no more than 28 days prior to enrollment. 9. Is willing and able to provide adequate fresh or archival tumor samples with sufficient quantity and tissue quality. A mandatory newly obtained pretreatment biopsy is required, if not clinically contraindicated and at an acceptable risk as determined by the investigator. If newly obtained tissue samples are not possible to obtain, archival tissue obtained from a lesion not previously irradiated and collected after the most recent prior therapy is acceptable. 10. A male participant capable of producing sperm is eligible to participate if he agrees to the following during the intervention period and for at least the time needed to eliminate each trial intervention. The length of time required to continue contraception after the last dose for each trial intervention is 3 months. * Must not freeze or donate sperm starting at screening and throughout the Treatment Period, and for at least 3 months after the final trial intervention administration. Note: Preservation of sperm should be considered before enrollment in this trial. • Adhere to either of the following contraception methods: * True abstinence from penile-vaginal intercourse, when this is in line with the preferred and usual lifestyle of the participant, OR * Uses a penile/external condom when having penile-vaginal intercourse with an NPOCBP, PLUS partner use of an additional contraceptive method, as a condom may break or leak Contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical trials. If the contraception requirements in the local label for any trial interventions are more stringent than those above, the local label requirements are to be followed. Key Exclusion Criteria: The clinical site will screen for the full exclusion criteria per protocol. 1. Prior treatment with any epigenetic agents including but not limited to EZH1, EZH2, EZH1/2, or PRC2 inhibitors. 2. Has a super scan as seen in the baseline bone scan. A super scan is defined as an intense symmetric activity in the bones and diminished renal parenchymal activity on baseline bone scan, such that the presence of additional metastases in the future could not be evaluated. 3. Clinically active brain metastases, spinal cord compression, or leptomeningeal carcinomatosis, defined as untreated or symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms. 4. Uncontrolled or significant cardiovascular disease, 5. Prior malignancy, active within the previous 3 years except for locally curable cancers that have been apparently cured or successfully resected, such as basal or squamous cell carcinoma, superficial bladder cancer, carcinoma in situ of the stomach, or carcinoma in situ of the breast. 6. Has active or uncontrolled HBV infection. 7. Has active or uncontrolled HCV infection. 8. Has active or uncontrolled HIV infection.