Supraphysiological Androgen to Enhance Treatment Activity in Metastatic Castration-Resistant Prostate Cancer, SPECTRA Study

Inclusion Criteria:

• Must be willing to provide informed consent prior to any study specific procedures

• Age >= 18 years

• Documented histologically confirmed adenocarcinoma of the prostate

• Patient must have evidence of castration resistant prostate cancer as evidenced byPSA progression (per Prostate Cancer Working Group 3 [PCWG3] criteria) and acastrate serum testosterone level (i.e., =< 50 mg/dL)

• PSA must be at least 2 ng/ml and rising on two successive measurements at least twoweeks apart

• Patients must have progressed on at least one prior next-generation androgenreceptor-signalling inhibitor (e.g., abiraterone, enzalutamide, etc.). There must beat least a 2-week washout period after stopping the most recent approved therapy formetastatic castration-resistant prostate cancer (mCRPC) (e.g., abiraterone,enzalutamide, Ra-223, sipuleucel-t) prior to cycle 1, day 1. If applicable, patientsshould be weaned off steroids at least 1 week prior to starting treatment

• Subjects enrolling to Cohort 3 must demonstrate evidence of PSMA expression on 68Ga-PSMA-11 PET as defined in the VISION trial

• No prior chemotherapy for the treatment of mCRPC. Patients may have receiveddocetaxel for the treatment of hormone-sensitive prostate cancer

• Prior treatment with non-chemotherapy investigational agents is permitted. Theremust be at least a 2-week washout period after stopping any investigational canceragent prior to cycle 1, day 1

• Hemoglobin >= 9 g/dL with no blood transfusion in the past 28 days (within 30 daysprior to administration of study treatment)

• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (within 30 days prior toadministration of study treatment)

• Platelet count >= 100 x 10^9/L (within 30 days prior to administration of studytreatment)

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within 30 daysprior to administration of study treatment)

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) /alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 2.5x institutional upper limit of normal unless liver metastases are present in whichcase they must be =< 5x ULN (within 30 days prior to administration of studytreatment)

• Patients must have creatinine clearance estimated using the Cockcroft-Gault equationor based on 24 hour urine test of >= 51 mL/min (within 30 days prior toadministration of study treatment)

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2

• Patients must have a life expectancy >= 16 weeks

• Patient is willing and able to comply with the protocol for the duration of thestudy including undergoing treatment and scheduled visits and examinations

• At least one lesion (measurable and/or non-measurable) that can be accuratelyassessed at baseline by CT, positron emission tomography (PET), magnetic resonanceimaging (MRI) and/or bone scan and is suitable for repeated assessment

• Must be willing to undergo metastatic biopsy and have a lesion amenable for biopsy

• Male patients and their partners, who are sexually active and of childbearingpotential, must agree to the use of two highly effective forms of contraception incombination, throughout the period of taking study treatment and for 6 months afterlast dose of study drug(s) to prevent pregnancy in a partner

Exclusion Criteria:

• Involvement in the planning and/or conduct of the study

• Other malignancy unless curatively treated with no evidence of disease for >= 2years except: adequately treated non-melanoma skin cancer, non-muscle invasivebladder cancer

• Persistent toxicities (Common Terminology Criteria for Adverse Event (CTCAE) grade >

2. caused by previous cancer therapy, excluding alopecia

• Patients with symptomatic uncontrolled brain metastases. A scan to confirm theabsence of brain metastases is not required. Patients with spinal cord compressionunless considered to have received definitive treatment for this and evidence ofclinically stable disease for 28 days

• Use of corticosteroids at a dose equivalent to > 10 mg of prednisone daily

• Planning to receive concurrent treatment with another systemic cancer therapy, asidefrom a luteinizing hormone releasing hormone (LHRH) analogue

• Use of warfarin is not permitted. Low-molecular weight heparin and direct oralanticoagulants are allowed, but their use should be discussed with the principalinvestigator (PI) first

• Major surgery within 2 weeks of starting study treatment and patients must haverecovered from any effects of any major surgery

• Patients considered a poor medical risk due to a serious, uncontrolled medicaldisorder, non-malignant systemic disease or active, uncontrolled infection. Examplesinclude, but are not limited to, uncontrolled ventricular arrhythmia, uncontrolledmajor seizure disorder, uncontrolled hypertension (blood pressure [BP] >= 165/100),history of prior stroke, unstable spinal cord compression, superior vena cavasyndrome, extensive interstitial bilateral lung disease or any psychiatric disorderthat prohibits obtaining informed consent

• Patients with a known hypersensitivity to the testosterone cypionate, etoposide,carboplatin or any of the excipients of these products

• Patients with known active hepatitis (i.e., hepatitis B or C) due to risk oftransmitting the infection through blood or other body fluids

• Evidence of serious and/or unstable pre-existing medical, psychiatric or othercondition (including laboratory abnormalities) that could interfere with patientsafety or provision of informed consent to participate in this study

• Any psychological, familial, sociological, or geographical condition that couldpotentially interfere with compliance with the study protocol and follow-up schedule

• Evidence of disease that, in the opinion of the investigator, would put the patientat risk from testosterone therapy (e.g. femoral metastases with concern overfracture risk, spinal metastases with concern over spinal cord compression, lymphnode disease with concern for ureteral obstruction)

• Patients with pain attributable to their prostate cancer.

• Excluded due to concern for pain flare due to testosterone supplementation

• Tumor causing urinary outlet obstruction that requires catheterization for voiding.Patients that require catheterization to void secondary to benign strictures orother non-cancer causes will be permitted to enroll. Patients with percutaneousnephrostomy tubes will also be permitted to enroll

• Prior history of deep venous thrombosis or pulmonary embolism within 5 years priorto enrollment in the study and not currently on systemic anticoagulation.

• Excluded due to risk of venous thromboembolism from hormone supplementation

• Patients with NYHA (New York Heart Association) class III or IV heart failure orhistory of a prior myocardial infarction (MI) within 5 years of enrollment to thestudy.

• Excluded due to increased risk of cardiovascular events with testosteronesupplementation