Phase 2a Study of High-Dose Testosterone Followed by Radioligand Therapy in mCRPC

• Testosterone cypionate (Tc) (Drug): IM injection of Tc at 400 mg (Tc400) every 28 days for up to 3 doses.
• ADT with Luteinizing hormone-releasing hormone (LHRH) analog (Drug): Continuing ADT with either surgical castration or chemical castration with LHRH analog is considered standard of care for mCRPC.
• PSMA-617 (Drug): IV at 7.4GBq (200mCi) once every 6 weeks for up to 6 doses.

Primary outcomes

• Feasibility of Tc400 and PSMA-617 [Up To 6 Months]: Percentage of patients who can complete 3 doses of Tc400 followed by at least 2 doses of PSMA-617.

Secondary outcomes

• Reduction in P/T ratio [Up To 6 Months]: Percentage of evaluable patients with 50% reduction in P/T ratio (PT50) compared to baseline P/T ratio based on PSA and testosterone values at screening.
• PSA50 and PSA 90 [Up To 6 Months]: Percentage of patients who achieved PSA50 and PSA 90 responses after two doses of PSMA-617 compared to the pre PSMA-617 PSA values at day 60.

Sex: Male, ages: 18 Years to any

Inclusion Criteria:

* Participants must have histologically or cytologically confirmed prostate cancer that has progressed to mCRPC with no grade 2 or above cancer related symptoms.
* Participants need to have either PSA or imaging progression at castrate level of serum testosterone (i.e. <50ng/dl). The definition of PSA progression and the definitions of imaging progression on measurable or non-measurable lesions will be based on the prostate cancer working group 3 (PCWG3) criteria. Patients with symptomatic oligo progression (1-3 sites), the symptoms need to be improved to grade 1 or less with palliative local therapy prior to study enrollment.
* Participants need to have a positive PSMA PET scan and deem eligible for PSMA-617.
* Allowable prior therapies: Prior treatment with one line of ARPI. Patients need to be on ARPI for at least 4 weeks to be considered one line of therapy. Prior treatment with sipuleucel-T for mCRPC. Prior treatment with docetaxel in the castration sensitive setting.
* ECOG performance status 0-1.
* Participants must have adequate organ and marrow functions.
* Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
* Participants with h/o myocardial infarction or history of congestive heart failure, need to have estimated left ventricle ejection fraction above 40% either on echocardiogram or MUGA scan within 6 months of study enrollment.
* Non-sterilized men who are sexually active with a female partner of childbearing potential treated or enrolled on this protocol must agree to use adequate contraception prior to the study, for the duration of study participation, and for 6 weeks after last dose of enzalutamide or docetaxel administration.
* Ability to understand and the willingness to sign a written informed consent document or have a legally authorized representative sign on the subject's behalf. Stated willingness to comply with all study procedures and availability for the duration of the study.

Exclusion Criteria:

* Metastatic prostate cancer with known epidural, liver or brain metastases.
* No history of cord compression.
* Treatment with radiation within 30 days prior to the first dose of Tc400.
* Receiving any other investigation agents. Prior treatment with investigation agents need to have a washout period of 4 weeks prior to enrollment.
* Participants with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, delayed healing of wounds, ulcers, or bone fractures, or psychiatric illness/social situations that would limit compliance with study requirements.

• Jingsong Zhang, MD, PhD, Principal investigator, Moffitt Cancer Center