Docetaxel and Hormone Treatment Compared to Hormone Treatment Alone in People with Metastatic Castration Sensitive Prostate Cancer and Less than Optimal PSA Response, TRIPLE-SWITCH Trial

Inclusion Criteria

• Male ≥ 18 years of age.
• Histologically/cytologically confirmed adenocarcinoma of prostate.
• Metastatic disease by conventional imaging (bone scan and/or computed tomography [CT]). PET-PSMA scan is allowed only if CT component is of diagnostic quality. Importantly, disease must be present based on conventional imaging (CT and/or bone scan) for enrollment on the study.
• PSA of ≥ 5.0 ng/ml (5.0 ug/L) prior to commencement of ADT.
• Receipt of ADT for mCSPC for at least 6 months and no greater than 12 months at time of enrollment.
• Receipt of ARPI (e.g. abiraterone acetate, enzalutamide, apalutamide, or darolutamide) for at least 4 months at time of enrollment.
• Potential trial participants should have recovered from clinically significant adverse events of their most recent therapy/intervention prior to enrollment.
• Serum testosterone < 1.7 nmol/L or 50 ng/dL.
• PSA ≥ 0.2 ng/ml (0.2 ug/L) within 14 days of enrollment. If there is any rise in PSA since starting ADT and achieving castrate-level testosterone, PSA must be repeated and must not fulfill ineligibility criteria.
• Candidate for docetaxel chemotherapy (per investigator).
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 2.
• Hemoglobin ≥ 90 g/dL (within 14 days prior to enrollment)
• Absolute neutrophils ≥ 1.5 x 10^9/L (within 14 days prior to enrollment)
• Platelets ≥ 100 x 10^9/L (within 14 days prior to enrollment)
• Total bilirubin ≤ 1.0 x upper limit of normal (ULN) (within 14 days prior to enrollment)
• Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 1.5 x ULN if no liver involvement or < 5.0 x ULN if liver metastases are present (within 14 days prior to enrollment) * With concurrent alkaline phosphatase ≤ 2.5 times the ULN
• Creatinine clearance ≥ 30 mL/min, measured directly by 24-hour urine sampling OR as calculated by Cockcroft and Gault equation (within 14 days prior to enrollment). * If suspected Gilbert’s, eligible providing a total bilirubin ≤ 2.0 x ULN
• Participant consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each participant must sign a consent form prior to enrollment in the trial to document their willingness to participate.
• Participants must be accessible for treatment and follow-up. Investigators must assure themselves the participants enrolled on this trial will be available for complete documentation of the treatment, adverse events, and follow-up.
• In accordance with Canadian Cancer Trials Group (CCTG) policy, protocol treatment is to begin within 5 working days of participant enrollment.
• If the participant and the participant’s partner are of childbearing potential, they must agree to use medically accepted methods of contraception (e.g. barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 90 days after the last dose of study drug.
• HIV-infected participants on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
• Participant access to all protocol therapies must be confirmed prior to enrollment.

Exclusion Criteria

• Two consecutive rises in PSA since achieving castration on ADT at least 2 weeks apart with at least one PSA ≥ 5% above the PSA nadir and with at least one PSA having an absolute increase of ≥ 0.5 ng/ml above the PSA nadir.
• Evidence of radiographic progression or clinical progression since start of ADT.
• Docetaxel criteria: * Prior treatment with taxane chemotherapy. * Grade 2 or worse peripheral neuropathy. * Severe hypersensitivity to drugs formulated with polysorbate 80.
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class II or better. * Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make this protocol unreasonably hazardous.
• Patients with a prior or concurrent malignancy whose natural history of treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
• Concurrent treatment with other anti-cancer systemic therapy other than ADT and ARPI.
• Live attenuated vaccination administered within 30 days prior to enrollment/randomization. * Note: Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and not allowed.
• For participants with history of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
• Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
• High-grade neuroendocrine prostate cancer or small cell features.