Cabazitaxel +/- Carboplatin vs 177Lu-PSMA-617 in Metastatic Castrate-resistant Prostate Cancer

Brief Background/Rationale

Metastatic prostate cancer initially is very responsive to androgen deprivation therapy (ADT), with intensification using an androgen receptor pathway inhibitor (ARPI) such as abiraterone acetate, enzalutamide, apalutamide, or darolutamide with or without docetaxel to prolong sensitivity to treatment and overall survival. Over time, however, prostate cancer transitions from castrate-sensitive to castrate-resistant. Metastatic castrate-resistant prostate cancer (mCRPC) has a dismal prognosis, with a median survival of under three years. There are now several agents with diverse mechanisms of action approved for use in mCRPC including cabazitaxel, sipuleucel-T, abiraterone acetate, enzalutamide, radium-223, olaparib, rucaparib, and 177Lu-PSMA-617.

Despite the treatment advances in the past decade, many cases of mCRPC either do not respond to these treatments or only respond for a short period of time. Predictive biomarkers are needed. In addition, with several options available, it is not always clear the optimal sequencing of these agents.

Inclusion criteria

• Participants must have histologically or cytologically confirmed adenocarcinoma of prostate
• Evidence of metastatic castrate-resistant prostate cancer that has previously been treated with an androgen receptor pathway inhibitor. Prior docetaxel exposure is recommended but not mandatory. Tissue is not mandatory, but a pathologic report is required at time of enrollment.
• Patients must have a PSMA-positive 18F-rhPSMA-7.3 performed within 12 weeks from C1D1 with ≥1 site with SUVmax ≥10. An alternative PSMA PET tracer is permitted at baseline if performed within 8 weeks prior to randomization.
• Eligible patients have evidence of mCRPC who have progressed on prior novel hormonal agent(s) to include at least one of the following:

• Baseline PSMA SUVmean <10 OR
• ≥1 visceral metastasis OR
• ≥5 bone metastases OR one of the following (using Next Generation Sequencing on file within 5 years)
• TP53
• PTEN
• mutation.
• Age > 18 years.
• ECOG performance status of 0 to 2.
• Participants must have adequate organ and marrow function as defined below to be suitable for the randomized treatment outlined in this

• Absolute neutrophil count >1000/μL; platelet count >90 000/μL; hemoglobin >8.5 g/dL) at screening.
• Note: Participants must not have received any growth factors within 7 days or blood transfusions within 14 days prior to the hematologic laboratory values obtained at screening).
• Total bilirubin (TBIL) <2.5 × the upper limit of normal (ULN) at screening, except participants with documented Gilbert syndrome who must have a TBIL <3 mg/dL
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 5 ULN at screening
• Creatinine clearance ≥40 mL/min and/or estimated glomerular filtration rate (eGFR) ≥30
• Albumin >30 g/L (3.0 g/dL) at screening
• Participants receiving bisphosphonates or other approved bone-targeting therapy (e.g., denosumab) must be on a stable dose for at least 14 days before the start of study treatment.
• Participants of child-producing potential agree to use highly effective contraceptive methods (i.e., barrier contraception measures such as a male condom with spermicide during intercourse) and avoid sperm donation during the study treatment and for 3 months after the last dose of study treatment. A man is considered to be of child-producing potential, unless he has had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy. Partners of patients must also practice approved forms of birth control
• Participants must have the ability to understand and the willingness to sign a written informed consent form (ICF).
• Members of all races and ethnic groups are eligible for this trial

Exclusion criteria

• Evidence of hormone-sensitive prostate cancer (HSPC)
• Evidence of small cell prostate cancer
• Participants receiving any other investigational agents.
• Diagnosis of another clinically significant malignancy within the previous 2 years other than curatively treated non-melanomatous skin cancer or superficial urothelial carcinoma and other in situ or noninvasive malignancies, as determined by the PI or Co-PI.
• Participants with brain metastases/central nervous system (CNS) disease that are treated prior to enrollment will be allowed in this clinical trial.
• Known or suspected significant hypersensitivity to any components of the formulation used for Cabazitaxel, carboplatin or 177Lu-PSMA-617.
• Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations considered by the Investigator to limit compliance with study requirements.
• Prior treatment toxicities not resolved to ≤ Grade 2 according to NCI CTCAE Version 5.0