Pembrolizumab, Carboplatin and Cabazitaxel in Aggressive Metastatic Castration Resistant Prostate Cancer (PEAPOD_FOS)

Inclusion Criteria:

• Male participants who are at least 18 years of age on the day of signing informedconsent

• Histologically confirmed diagnosis of adenocarcinoma and/or neuroendocrine carcinomaof the prostate will be enrolled in this study

• Presence of metastatic disease documented on imaging studies (bone scan, computedtomography (CT) and/or magnetic resonance imaging (MRI) scans

• At least one of the following Aggressive Variant Prostate Cancer (AVPC) Criteria

1. Histologically proven small cell (neuroendocrine) prostate cancer

2. Exclusive visceral metastases

3. Predominantly lytic bone metastases

4. Bulky lymph nodes (≥ 5 cm in longest dimension) or high-grade pelvic/prostaticmasses

5. Low PSA (≤10 ng/ml) at initial presentation in the presence of extensivedisease (≥20 metastases)

6. Elevated serum Lactate Dehydrogenase (LDH) (≥2 x ULN) or carcinoembryonicantigen (CEA) (≥2 x Upper limit (UL))

7. Short time to castration-resistance (≤6 months).

• Male participants: a male participant must agree to use a contraception as detailedin Appendix 3 of the protocol during the treatment period and for at least after thelast dose of study treatment and refrain from donating sperm during this period

• The participant (or legally acceptable representative if applicable) provideswritten informed consent for the trial.

• Have measurable disease based on RECIST 1.1. Lesions situated in a previouslyirradiated area are considered measurable if progression has been demonstrated insuch lesions.

• Have provided archival tumor tissue sample obtained in the previous year since ornewly obtained core or excisional biopsy of a tumor lesion not previouslyirradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred toslides. Newly obtained biopsies are preferred to archived tissue.

• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.Evaluation of ECOG is to be performed within 7 days prior to the first dose of studyintervention.

• Have adequate organ function as defined in the table 1 of the protocol. Specimensmust be collected within 10 days prior to the start of study intervention.

• Criteria for known Hepatitis B (HBV) and C (HCV) positive subjects

1. Hepatitis B and C screening tests are not required unless:

• Known history of HBV or HCV infection
• As mandated by local health authority

2. Hepatitis B positive subjects

• Participants who are HBsAg positive are eligible if they have received HBVantiviral therapy for at least 4 weeks and have undetectable HBV viralload prior to randomization.
• Participants should remain on anti-viral therapy throughout studyintervention and follow local guidelines for HBV anti-viral therapy postcompletion of study intervention.

3. Participants with history of HCV infection are eligible if HCV viral load isundetectable at screening. • Participants must have completed curativeanti-viral therapy at least 4 weeks prior to randomization.

Exclusion Criteria:

• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent orwith an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4), OX-40, CD137).

• Has received prior systemic anti-cancer therapy including investigational agentswithin 4 weeks prior to informed consent signature.

• Has received previous treatment with cabazitaxel or carboplatin.

• Has received prior radiotherapy within 2 weeks of start of study intervention.Participants must have recovered from all radiation-related toxicities, not requirecorticosteroids, and not have had radiation pneumonitis. A 1-week washout ispermitted for palliative radiation (≤2 weeks of radiotherapy) to non-central nervoussystem (non-CNS) disease.

• Has received a live vaccine or live-attenuated vaccine within 30 days before thefirst dose of study intervention. Administration of killed vaccines is allowed.

• Is currently participating in or has participated in a study of an investigationalagent or has used an investigational device within 4 weeks prior to the first doseof study intervention.

• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form ofimmunosuppressive therapy within 7 days prior to the first dose of study drug.

• Known additional malignancy that is progressing or has required active treatmentwithin the past 5 years. Note: Participants with basal cell carcinoma of the skin,squamous cell carcinoma of the skin or carcinoma in situ, excluding carcinoma insitu of the bladder, that have undergone potentially curative therapy are notexcluded.

• Has known active CNS metastases and/or carcinomatous meningitis. Participants withpreviously treated brain metastases may participate provided they are radiologicallystable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening),clinically stable and without requirement of steroid treatment for at least 14 daysprior to first dose of study intervention.

• Has severe hypersensitivity (≥Grade 3) to pembrolizumab, carboplatin or cabazitaxeland/or any of its excipients.

• Has active autoimmune disease that has required systemic treatment in the past 2years (i.e., with use of disease modifying agents, corticosteroids orimmunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment and is allowed.

• Has a history of (non-infectious) pneumonitis/interstitial lung disease thatrequired steroids or has current pneumonitis/interstitial lung disease.

• Has an active infection requiring systemic therapy

• Has congestive Heart failure New York Heart Association (NYHA) ≥2.

• Has hypoacusis grade ≥2.

• Has a known history of Human Immunodeficiency Virus (HIV) infection

• Concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV DNA)and Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA)infection.

Note: Hepatitis B and C screening tests are not required unless:

• Known history of HBV and HCV infection

• As mandated by local health authority

• Has a history or current evidence of any condition, therapy, or laboratoryabnormality or other circumstance that might confound the results of the study,interfere with the participant's participation for the full duration of thestudy, such that it is not in the best interest of the participant toparticipate, in the opinion of the treating investigator.

• Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial.

• Has had an allogenic tissue/solid organ transplant.