This study will follow men with metastatic castration resistant prostate cancer throughout their standard of care treatment for their disease to determine if the presence of different genes or proteins can predict which patients respond to the cancer treatment they receive. As tumors grow and begin to spread, they may release cells into patients' bloodstream. These cells are called "circulating tumor cells", or CTCs. CTCs can be used to look for differences in "biomarkers" (genes or proteins that may change based on how a person is or is not responding to treatment). The purpose of this research study is to learn whether scientists can use biomarkers from CTCs to predict which tumors will respond to certain hormonal therapies. Participants will have blood collected and provide an archival sample from a previous tumor biopsy. The researchers will compare biomarkers from participants who responded well to treatment to those who responded poorly in order to answer the research question.

Inclusion Criteria:

Patients will be eligible for inclusion in this study only if all of the following criteria apply:

1. Histologically confirmed diagnosis of adenocarcinoma of the prostate. Patients with pure small cell/neuroendocrine tumors of the prostate are not permitted.

2. Radiographic evidence of metastatic disease by CT, MRI, or PET imaging.

3. Prior documented disease progression on one potent AR inhibitor (darolutamide, abiraterone, enzalutamide, or apalutamide or combinations of these) in any disease setting (mHSPC, nmCRPC, mCRPC) based on sequential PSA rises or radiographic progression.

4. Planned therapy with either standard of care enzalutamide and/or abiraterone acetate or another potent AR inhibitor (darolutamide, apalutamide if available) within the coming 6 weeks

5. Castrate levels of testosterone (<50 ng/dl) at most recent assessment and/or documented ongoing Androgen Deprivation Therapy.

6. Evidence of disease progression based on a rising PSA on or following most recent therapy as evidenced by the following:

   1. Consecutive PSA rises at least 2 weeks apart
   2. Minimum PSA of 1.0 ng/dl prior to entry

7. Age > 18 years.

8. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

A patient will not be eligible for inclusion in this study if any of the following criteria apply:

1. History of intercurrent or past medical or psychiatric illness including active stage IV malignancy that would make participation in a blood drawing protocol difficult or not feasible at the discretion of the principal investigator or co-investigator(s).
2. Unwillingness to be followed longitudinally for serial CTC biomarker studies.
3. Life expectancy < 6 months
4. Planned combination therapy with radiation or other systemic therapies other than ADT and bone health agents.

The study population includes men with progressive metastatic castration resistant prostate cancer (mCRPC) as defined in the eligibility criteria listed below. Participants will enroll at one of three locations: Duke University, University of Wisconsin Madison and Memorial Sloan Kettering Cancer Center.