Neo-DAB: Darolutamide and Abemaciclib in Prostate Cancer

This research study is trying to determine the safety and efficacy of the combination of two oral drugs, abemaciclib and darolutamide, with androgen deprivation therapy (ADT) in the treatment of metastatic, non-metastatic, and advanced prostate cancers. The first phase of the study is to establish a recommended dose for the second phase. The names of the study drugs and interventions involved in this study are: * Darolutamide * Abemaciclib * Androgen deprivation therapy (ADT) - this includes several different treatments, including Gonadotropin-Releasing Hormone (GnRH) antagonists and agonists It is expected that about 93 people will take part in the research study. Treatment is expected to last 6 months with a follow up period of up to 4.5 years.

Inclusion Criteria For Phase 1: * Provision of signed informed consent prior to any study specific procedures, or have a legally authorized representative sign on the participant's behalf. * Ability to swallow oral medications and comply with study procedures and requirements. * Males ≥18 years * Histologically or cytologically confirmed adenocarcinoma of the prostate without histologic variants (including neuroendocrine differentiation, small cell, sarcomatoid, ductal adenocarcinoma, squamous or transitional cell carcinoma) comprising \>50% of the sample as determined by academic medical center pathology review; men without histologic confirmation are eligible provided there is unequivocal evidence of prostate cancer (eg. very high PSA) in the view of the treating physician. * M0 or M1 (by CT/MRI and bone scans) CRPC with evidence of progression at study entry demonstrated during continuous androgen deprivation therapy (LHRH/GnRH agonists/antagonists/post orchiectomy) and castrate level of serum testosterone (≤50 ng/dl). Progression is defined as one or more of the following: * Sequence of at least 2 rising PSA values at a minimum of 1-week intervals with the last result being at least 1.0 ng/mL if confirmed PSA rise is the only indication of progression. Patients who received an anti-androgen (flutamide, bicalutamide or nilutamide) must have PSA progression ≥4 weeks after the last dose. * Radiographic progression per RECIST 1.1 for soft tissue and/or per PCWG3 for bone (i.e., appearance of ≥2 new bone lesions), with or without PSA progression. * Serum testosterone level must be ≤50 ng/dL (1.73 nmol/L) at the screening visit. Participants who have not undergone bilateral orchiectomy are required to continue LHRH/GnRH agonists/antagonists) throughout the study. * ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A). * Participants must have adequate organ and marrow function as below: * System Laboratory Value * Hematologic * ANC ≥1.5×109/L * Platelets ≥100×109/L * Hemoglobin ≥9g/dL (≥90g/L) independent of transfusions * Hepatic * Total Bilirubin ≤1.5 × ULN OR \50% of the sample as determined by academic medical center pathology review. * ≥3 biopsy cores (either systematic or targeted, or a combination) involved with prostate cancer. Prostate biopsy must have been performed within 6 months of screening. \1cm of tumor or ≥cT3 disease on MRI prostate. * Participants must have at least 1 biopsy core with either: * Gleason ≥8 OR * Gleason 4+3=7 AND at least one of the following: * PSA \>20ng/dL * ≥cT3 disease by MRI * Evidence of EPE on biopsy * No evidence of metastatic disease as determined by radionuclide bone scan and CT/MRI, and/or PSMA-PET. Pelvic lymph nodes \