A Phase 3, Randomized, Open-Label, Controlled Study of Cabozantinib (XL184) in Combination with Atezolizumab vs Second Novel Hormonal Therapy (NHT) in Subjects with Metastatic Castration-Resistant Prostate Cancer

INTERVENTION: Product Name: Cabozantinib 20mg Product Code: XL184 Pharmaceutical Form: Tablet INN or Proposed INN: CABOZANTINIB CAS Number: 1140909‐48‐3 Current Sponsor code: XL184 Other descriptive name: XL184 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 20‐ Product Name: Atezolizumab Pharmaceutical Form: Concentrate for solution for infusion INN or Proposed INN: ATEZOLIZUMAB Other descriptive name: RO5541267 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 60‐ Product Name: Abiraterone acetate Pharmaceutical Form: Tablet INN or Proposed INN: Abiraterone CAS Number: 154229‐18‐2 Other descriptive name: ABIRATERONE ACETATE Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 500‐ Product Name: Enzalutamide Pharmaceutical Form: Capsule, soft INN or Proposed INN: ENZALUTAMIDE CAS Number: 915087‐33‐1 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 40‐ Product Name: Prednisone Pharmaceutical Form: Tablet INN or Proposed INN: PREDNISONE Other descriptive name: PREDNISONE Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 5‐ CONDITION: Metastatic Castration‐Resistant Prostate Cancer ; MedDRA version: 21.1 Level: LLT Classification code 10076506 Term: Castration‐resistant prostate cancer System Organ Class: 100000004864 Therapeutic area: Diseases [C] ‐ Cancer [C04] PRIMARY OUTCOME: Main Objective: To evaluate the efficacy of cabozantinib in combination with atezolizumab versus second NHT (abiraterone or enzalutamide) in subjects with first or; second line mCRPC who have previously received one and only one NHT (eg, abiraterone, apalutamide, darolutamide, or enzalutamide) to treat mCSPC, M0 CRPC, or mCRPC, and who have measurable visceral disease or measurable extrapelvic adenopathy. Primary end point(s): • Duration of PFS per RECIST 1.1 per BIRC; • Duration of OS Secondary Objective: Not applicable Timepoint(s) of evaluation of this end point: • The primary analysis of PFS is event‐driven and will be conducted after at least 202 events have been observed in the PITT population.; • The primary analysis of OS is event‐driven and will be conducted after at least 340 deaths have been observed in the ITT population. SECONDARY OUTCOME: Secondary end point(s): • ORR per RECIST 1.1 per BIRC Timepoint(s) of evaluation of this end point: At time of data cutoff, the proportion of subjects for whom the best overall response is a CR or PR as assessed by the BIRC per RECIST 1.1, which is confirmed by a subsequent visit = 28 days later. INCLUSION CRITERIA: 1. Men with histologically or cytologically confirmed adenocarcinoma of the prostate. 2. Prior treatment with one, and only one, NHT (eg, abiraterone, apalutamide, darolutamide, or enzalutamide) for castration‐sensitive locally advanced (T3 or T4) or metastatic castration‐sensitive prostate cancer, M0 CRPC, or mCRPC. 3. Bilateral orchiectomy or ongoing androgen deprivation therapy with a gonadotropin‐releasing hormone (GnRH) agonist/antagonist (surgical or medical castration), with serum testosterone = 50 ng/dL (= 1.73 nmol/L) at screening. 4. Measurable (extrapelvic soft tissue) metastatic disease per Investigator assessment as defined by at least one of the following: a. Measurable visceral (eg, adrenal, kidney, liver, lung, pancreas, spleen) disease per RECIST 1.1, OR b. Measurable extrapelvic adenopathy (ie, adenopathy above the aortic bifurcation). 5. Progressive disease at study entry as defined by at least one of the following two crit