Targeted Treatment for Metastatic Prostate Cancer, The PREDICT Trial

Inclusion Criteria:

• PRE-REGISTRATION: Histological or cytological evidence of prostate cancer. Patientswith variant histologies including neuroendocrine, small cell and sarcomatoidprostate cancer are allowed to enroll and these will not be used as selectioncriteria for individual arms. Central pathology review is not required.

• PRE-REGISTRATION: Measurable disease and/or non-measurable metastatic disease perRECIST version 1.1.

• PRE-REGISTRATION: Tissue procured within 12 months of pre-registration (metastaticdisease preferred over primary tissue, though both are acceptable) available forsubmission per Section 6.2. For patients who have progressed on A032102 and arepre-registering again, repeat tissue procurement will not be mandated.

• PRE-REGISTRATION: Molecular report available performed as part of standard of caretesting via any Clinical Laboratory Improvement Act (CLIA)-certified next generationsequencing (NGS) assay. Patients may be assigned based on pre-determined qualifyingmolecular/DNA alterations as stated in Section 4.8 after receipt of local moleculartesting by the A032102 molecular tumor board (MTB). Final determination of armassignment will be determined by the MTB. For qualifying DNA alteration determinedby the MTB, testing may be from tumor tissue collected at any time or circulatingtumor DNA (ctDNA) within 12 months of pre-registration. If no qualifying DNAalteration is identified based on the CLIA-certified next generation sequencingassay and MTB review, Caris testing, should be performed for both DNA/RNA profiling.Arm assignment based RNA requires testing of tumor tissue collected within 12 monthsof pre-registration and MTB review.

• PRE-REGISTRATION: Age ≥ 18 years.

• REGISTRATION: Progressive mCRPC as defined: 1) castrate levels of serum testosterone < 50 ng/dL AND one or more of the following criteria (choose all the apply):

• PSA progression, defined by at least 2 consecutive rising PSA values at aminimum of 1-week intervals with the most recent PSA value being 2.0 ng/mL orhigher, if confirmed PSA rise is the only indication of progression. Patientswho received an anti-androgen must have PSA progression after withdrawal ofanti-androgen therapy.

• Radiographic progression per RECIST 1.1 criteria for soft tissue lesions

• Bone metastasis progression per Prostate Cancer Working Group 3 (PCWG3)criteria.

• REGISTRATION: Patients selected to receive lutetium Lu 177 vipivotide tetraxetantreatment are required to have prostate-specific membrane antigen (PSMA) positivemCRPC as determined by investigator assessment. For reference, in the VISION trialthis was defined as at least 1 PSMA+ metastatic lesion (defined as uptake greaterthan that of liver parenchyma in lesions of any size in any organ system) and noPSMA- lesions (defined as uptake equal to or lower than that of liver parenchyma inany lymph node with a short axis of at least 2.5 cm, in any solid organ lesion witha short axis of at least 1.0 cm, or in any bone lesion with a soft-tissue componentof at least 1.0 cm in the short axis).

• REGISTRATION: Prior treatment with androgen receptor signaling inhibitor (ARSI) ineither the metastatic hormone sensitive setting or mCRPC is required. Prior taxanetherapy in either metastatic hormone sensitive setting or mCRPC is mandated unlesspatient is taxane ineligible or the patient refuses taxane therapy. Prior lutetiumLU177 vipivotide tetraxetan treatment is permitted but not mandated. Patients withknown germline or somatic deleterious BRCA 1/2 mutations must have received a priorPARPi.

• REGISTRATION: Resolved toxicities from previous anticancer therapy, defined astoxicities (other than alopecia) resolved to Common Terminology Criteria for AdverseEvents (CTCAE) version 5.0, grade ≤ 1 or baseline. Note: Subjects may be enrolledwith chronic, stable grade 2 toxicities (defined as no worsening to > grade 2 forat least 3 months prior to registration and managed with standard of care treatment)that the investigator deems related to previous anticancer therapy, comprised of:

• Chemotherapy-induced neuropathy

• Fatigue

• Residual toxicities from prior treatment: Grade 1 or grade 2 endocrinopathieswhich may include: Hypothyroidism/hyperthyroidism. type I diabetes,hyperglycemia, adrenal insufficiency, adrenalitis, skin hypopigmentation (vitiligo)

• REGISTRATION: No cytotoxic, biologic, radiopharmaceutical or other non-kinaseinhibitor investigational agent within 4 weeks of registration. Treatment with anytype of small molecular kinase inhibitor (including investigational kinaseinhibitor) within 2 weeks of registration. Treatment with abiraterone acetate,apalutamide, or darolutamide within 2 weeks of registration. Treatment withenzalutamide within 4 weeks of registration. No treatment with radiation therapywithin 2 weeks of registration.

• REGISTRATION: No major surgery within 4 weeks of registration.

• REGISTRATION: No prior treatment with EZH inhibitors.

• REGISTRATION: Prior treatment with cabazitaxel + carboplatin.

• REGISTRATION: None of the following conditions:

• Current use of moderate or strong cytochrome P450 (CYP)3A inducers.

• Known or suspected hypersensitivity to valemetostat tosylate (DS-3201b) or anyof the excipients.

• For patients with evidence of chronic hepatitis B virus (HBV) infection, theHBV viral load must be undetectable on suppressive therapy, if indicated.Patients with a history of hepatitis C virus (HCV) infection must have beentreated and cured. For patients with HCV infection who are currently ontreatment, they are eligible if they have an undetectable HCV viral load.

• HIV-infected patients on effective anti-retroviral therapy with undetectable viralload within 6 months are eligible for this trial.

• Imminent or established spinal cord compression based on clinical and/orimaging findings.

• Known brain metastases or cranial epidural disease unless adequately treatedwith radiotherapy and/or surgery (including radiosurgery) and stable for atleast 4 weeks prior to registration after radiotherapy or at least 4 weeksprior to registration after major surgery (e.g., removal or biopsy of brainmetastasis). Patients must have complete wound healing from major surgery orminor surgery before registration.

• Significant cardiovascular defined as:

• Myocardial infarction within 6 months prior to enrollment.

• Uncontrolled angina pectoris within 6 months prior to enrollment.

• New York Heart Association Class 3 or 4 congestive heart failure.

• Corrected QT interval calculated by the Fridericia's formula (QTcF) ≥ 470ms per electrocardiogram (ECG) within 42 days before randomization in anyindividual with any history of any cardiac disease or medication which canimpact QTcF. Patients with known history or current symptoms of cardiacdisease, history of treatment with cardiotoxic agents, or agents/conditionsknown to impact QTcF should have a clinical risk assessment of cardiac functionusing the New York Heart Association Functional Classification and ECG.

• Uncontrolled hypertension (resting systolic blood pressure >160 mmHg ordiastolic blood pressure > 100 mmHg).

• Clinically significant acute infection requiring systemic antibacterial,antifungal or antiviral therapy.

• Moderate to severe hepatic impairment (Child-Pugh Class C)

• REGISTRATION: No freezing or donating sperm ≤ 14 days prior to registration.

• REGISTRATION: Eastern Cooperative Oncology Group (ECOG) performance status 0-2.

• REGISTRATION: No granulocyte colony-stimulating factor (GCSF) within 2 weeks ofregistration.

• REGISTRATION: No red blood cell (RBC) transfusions within 2 weeks of registration.

• REGISTRATION: No platelet transfusions within 2 weeks of registration.

• REGISTRATION: No bleeding diathesis.

• REGISTRATION: White blood cell count (WBC) ≥ 2,500/mcL.

• REGISTRATION: Absolute neutrophil count (ANC) ≥ 1,500/mcL.

• REGISTRATION: Hemoglobin ≥ 9 g/dL.

• REGISTRATION: Platelet count ≥ 100,000/mcL.

• REGISTRATION: Creatinine clearance ≥ 30 mL/min as defined by Cockcroft-Gaultequation.

• REGISTRATION: Total bilirubin ≤ 1.5 x ULN (≤ 3 x upper limit of normal [ULN] forsubjects with documented Gilbert's disease).

• REGISTRATION: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN.

• REGISTRATION: Albumin ≥ 2.8 g/dL.

• REGISTRATION: The A032102 molecular tumor board will review the local pathologyreport and molecular sequencing report, and the Alliance registration/randomizationoffice will relay the assignment to the submitting site. Once the site receives thisassignment, they can register the patient to A032102. Any questions about themolecular board treatment assignments can be directed to A032102@alliancenctn.org.

• RE-REGISTRATION: Progressive mCRPC (after receiving the tumor board assignedtherapy) as defined: 1) castrate levels of serum testosterone < 50 ng/dL AND 2)progressive disease defined by radiographic progression on conventional imaging (CT/MRI chest, abdomen and pelvis and bone scan within 42 days of re-registration).

• RE-REGISTRATION: Resolved toxicities from previous anticancer therapy, defined astoxicities (other than alopecia) resolved to CTCAE version 5.0, grade ≤ 1 orbaseline. Note: Subjects may be enrolled with chronic, stable grade 2 toxicities (defined as no worsening to > grade 2 for at least 3 months prior to registrationand managed with standard of care treatment) that the investigator deems related toprevious anticancer therapy, comprised of:

• Chemotherapy-induced neuropathy

• Fatigue

• Residual toxicities from prior treatment: Grade 1 or grade 2 endocrinopathieswhich may include: Hypothyroidism/hyperthyroidism. type I diabetes,hyperglycemia, adrenal insufficiency, adrenalitis, skin hypopigmentation (vitiligo).

• RE-REGISTRATION: None of the following conditions:

• Imminent or established spinal cord compression based on clinical and/orimaging findings.

• Known brain metastases or cranial epidural disease unless adequately treatedwith radiotherapy and/or surgery (including radiosurgery) and stable for atleast 4 weeks prior to registration after radiotherapy or at least 4 weeksprior to re-registration after major surgery (e.g., removal or biopsy of brainmetastasis). Patients must have complete wound healing from major surgery orminor surgery before re-registration.

• Corrected QT interval calculated by the Fridericia's formula (QTcF) < 470 ms per ECG within 42 days before randomization in any individual with anyhistory of any cardiac disease or medication which can impact QTcF.

• Significant cardiovascular defined as:

• Myocardial infarction within 6 months prior to enrollment.

• Uncontrolled angina pectoris within 6 months prior to enrollment.

• New York Heart Association Class 3 or 4 congestive heart failure.

• Uncontrolled hypertension (resting systolic blood pressure > 160 mmHg ordiastolic blood pressure > 100 mmHg).

• RE-REGISTRATION: ECOG Performance Status 0-2.

• RE-REGISTRATION: No GCSF within 2 weeks of registration.

• RE-REGISTRATION: No RBC transfusions within 2 weeks of registration.

• RE-REGISTRATION: No platelet transfusions within 2 weeks of registration.

• RE-REGISTRATION: WBC ≥ 2,500/mcL.

• RE-REGISTRATION: ANC ≥ 1,500/mcL.

• RE-REGISTRATION: Hemoglobin ≥ 9 g/dL (transfusions permitted).

• RE-REGISTRATION: Platelet count ≥ 100,000/mcL.

• RE-REGISTRATION: Creatinine clearance ≥ 30 mL/min as defined by Cockcroft-Gaultequation.

• RE-REGISTRATION: Total bilirubin ≤ 1.5 x ULN (≤ 3 x ULN for subjects with documentedGilbert's disease).

• RE-REGISTRATION: AST and ALT ≤ 3 x ULN.

• RE-REGISTRATION: Albumin ≥ 2.8 g/dL.

• RE-REGISTRATION: QT Interval (QTcF) < 470 ms (in individuals with any cardiachistory of any medication or condition known to impact QTcF).

• RE-REGISTRATION: The A032102 molecular tumor board will review the CARIS molecularsequencing report, the Alliance registration/randomization office will relay theassignment to the site. Any questions about the molecular board treatmentassignments can be directed to A032102@alliancenctn.org.

Exclusion Criteria: