The goal of this clinical trial is to learn how exercise intervention affects circulating tumor cells (CTC) in men with advanced prostate cancer. The primary objective is to determine if an exercise intervention decreases CTCs in men with advanced prostate cancer. Participants will have baseline screening assessments, followed by 12 weeks of exercise intervention, and then follow-up assessments 12 weeks after the end of the exercise intervention.

This is a pilot single arm prospective study of personalized exercise training in men with metastatic castration resistant prostate cancer who are being treated with or without oral anti-androgens. The primary objective is to determine if combination of resistance and aerobic exercises lowers CTCs in men with mCRPC. Researchers will assess the rate of conversion from CTC positive to CTC negative in participants at the end of the 12 week exercise intervention. The study will enroll 20 participants onto the trial with the goal of at least 10 participants having blood drawn at both baseline and 12 weeks and completed at least 75% of the prescribed exercise sessions. Participants will undergo follow-up assessments at the end of the 12 week exercise intervention and the study team will monitor participant records for 365 days after the study completion for vital status.

Inclusion Criteria:

1. Men with metastatic prostate adenocarcinoma
2. Currently taking androgen deprivation therapy alone or with an oral androgen axis inhibitor (abiraterone, enzalutamide, darolutamide, or apalutamide are permitted) and have been on treatment for at least 3 months
3. Elevated (PSA > 1ng/mL) or rising PSA (any numerical increase based on at least 2 PSA readings at least 2 weeks apart)
4. Any number of prior therapies (prior chemo, radium-223, etc.) is allowed
5. CTC + according to standard clinical grade laboratory test by androgen receptor isoform splice variant 7 (AR-V7) testing at Hopkins.
6. If a bone protective agent is to be started, it should be started at least 2 weeks prior to the onset of exercise intervention.
7. Eastern Cooperative Oncology Group (ECOG) performance status <=1
8. Clearance by cardiologist if under the current care of a cardiologist (seen in the past 1 year)
9. Age <=80 years

Exclusion Criteria:

1. Small cell carcinoma of the prostate
2. Unable to participate or monitor exercise compliance due to conditions such as impaired cognition
3. Moderate to severe bone pain that limits any activities of daily living, including use of narcotics for prostate cancer related pain
4. Clinical progression requiring a change in systemic therapy or the addition of palliative radiation for symptom control
5. Bone metastases in spine or long bones which, in the eye of the treating physician require referral to radiation oncology or surgery for management due to risk of fracture
6. Significant cardiovascular disease or concurrent illness that would make exercise intervention for 12 weeks unsafe. If there is significant cardiovascular disease and the participant is under the care of a cardiologist (seen within the past 1 year), approval of the cardiologist to participate is required.
7. Major surgery within the past 4 weeks