• Participants must have histologically or cytologically confirmed prostate cancer. Either fresh biopsy or archival tissue can be used for confirmation.

• Age \>= 18 years.

• Patients must have metastatic castration resistant prostate cancer (mCRPC) with progression based on Prostate Cancer Working Group 3 (PCWG3) criteria.

• Patients must have adenocarcinoma histology.

• Prior treatment with at least one novel hormonal agents (NHA) such as abiraterone acetate, enzalutamide, apalutamide, darolutamide etc.

• Patients must have prior orchiectomy and/or ongoing androgen-deprivation therapy and a castrate level of serum testosterone (\< 50 ng/dL or \< 1.7 nmol/L)

• Patients must have a 68Ga-PSMA-11 PET scan with at least one PSMA-positive lesions (maximum standardized uptake value \[SUVmax\] greater than SUVmax of liver) as determined by nuclear medicine review prior to start of lead-in treatment with abemaciclib

• Patients must have Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2

• Patients must have life expectancy of \> 6 months

⁃ Patients must have adequate organ function as outlined below and bone marrow reserve

∙ White blood cell (WBC) \> 2.5

‣ Absolute neutrophil count (ANC) \> 1.5

‣ Hemoglobin (Hgb) \> 8.0 \[Note- Participants may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Initial treatment must not begin earlier than the day after the erythrocyte transfusion\]

‣ Platelets (Plt) \> 100,000

‣ Total bilirubin =\< 1.5 x the institutional upper limit of normal (ULN). For patients with known Gilbert's Syndrome =\< 2 ULN and direct bilirubin within normal limits is permitted

‣ Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase (SGOT)) =\< 3 X institutional upper limit of normal (=\< 5.0 ULN for patients with liver metastases)

‣ Alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase (SGPT)) =\< 3 X institutional upper limit of normal (=\< 5.0 ULN for patients with liver metastases)

‣ Creatinine =\< 1.5 x within institutional upper limit of normal OR creatinine clearance glomerular filtration rate (GFR) \>= 30 mL/min/1.73 m, calculated using the Cockcroft-Gault equation.

⁃ Patient must be able to swallow oral medications

⁃ Patients must have the ability to understand a written informed consent document, and the willingness to sign it

⁃ Human immunodeficiency virus (HIV)-infected individuals on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial

⁃ For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated

⁃ Individuals with a history of hepatitis C virus (HCV) infection must have been treated and cured. For individuals with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load

⁃ Individuals 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

⁃ Patients with reproductive potential must agree to use effective contraception and to not donate sperm during the study and for at least 2 months following the last dose of study treatment. Effective method of contraception means male condom with spermicide, female condom with spermicide, diaphragm with spermicide, cervical sponge, or cervical cap with spermicide