Neoadjuvant Darolutamide and Relugolix Combination Preceding Radical Prostatectomy for Prostate Cancer

Inclusion Criteria:

1. Histologically or cytologically confirmed adenocarcinoma of the prostate

2. ECOG performance status 0-1

3. Ability to swallow oral medications and comply with study procedures andrequirements.

4. Males ≥18 years

5. Participants must have adequate organ and marrow function as below:

6. Absolute neutrophil count (ANC) ≥1,500/mm3 or ≥1.5 x 109/L;

7. Platelets ≥100,000/mm3 or ≥100 x 109/L;

8. Hemoglobin ≥8 g/dL (may have been transfused).

9. Estimated creatinine clearance ≥30 mL/min as calculated using theCockcroft-Gault equation.

10. Total serum bilirubin <1.5 x upper limit of normal (ULN), less than 2.0 x ULN if suspected Gilbert's syndrome;

11. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than 2.5 x ULN.

12. Must be a candidate for RP

13. Clinical stage cT2-4, N0-1

14. Mandatory to identify tumor availability (≥10 FFPE slides, 5 µM thickness & 1stained H&E slide OR tumor block)

15. High-risk PCa defined as one of the following-

• Gleason score (GS) ≥ 4 + 3 with ≥ 6 positive systematic biopsies (SB)

• GS ≥ 4 + 3 with ≥ 3 SB and prostate-specific antigen (PSA) ≥ 20 ng/mL

• GS ≥ 9 in ≥ 1 SB or targeted biopsies (TB) -≥ 2 SB or TB with continuous GS ≥ 8, each with ≥ 80% involvement.

Exclusion Criteria:

1. Histologic variants including neuroendocrine differentiation, small cell,sarcomatoid, ductal adenocarcinoma, squamous or transitional cell carcinoma)comprising more than 50% of the sample as determined by pathology review

2. Participants who have had chemotherapy or radiotherapy within 4 weeks prior toplanned cycle 1 day 1 of study treatment.

3. Participants who have received anti-neoplastic intervention or experimentalantineoplastic therapy within 14 days of planned cycle 1 day 1 of study therapy.

4. Participants who are receiving any other investigational agents.

5. Participants who have previously received darolutamide, relugolix, LHRHagonist/antagonist or another novel androgen blocking therapy (abiraterone,apalutamide, enzalutamide) within 1 year are excluded (prior bicalutamide that wasdiscontinued ≥14 days prior to planned cycle 1 day 1 is allowed).

6. Participants who have not recovered from adverse events due to prior anti-cancertherapy (i.e. have residual toxicities ≥Grade 2) with the exception of alopecia.

7. Any of the following within 6 months before planned cycle 1 day 1 of study therapy:

• Stroke

• Myocardial infarction

• Severe/unstable angina pectoris

• Coronary/peripheral artery bypass graft

• Congestive heart failure New York Heart Association (NYHA) Class III or IV.

8. Known or suspected contraindications, hypersensitivity or allergy to darolutamide orrelugolix or to any of their excipients.

9. Participants with hepatitis C, hepatitis B or human immunodeficiency (HIV) who areon anti-viral therapy that has the potential to interact with darolutamide orrelugolix.

10. Participants treated with drugs known to be strong inhibitors and/or inducers ofcytochrome P450 3A4 (CYP3A4) and the treatment cannot be discontinued or switched toa different medication at least 5 half-lives prior to starting study drug.

11. NOTE: precaution is warranted with concomitant use of agents with a narrowtherapeutic index that are substrates of P-gp, BCRP and OCT1.

12. The participant has serious and/or uncontrolled preexisting medical condition(s)that, in the judgment of the investigator, would preclude participation in thisstudy (for example, interstitial lung disease, severe dyspnea at rest or requiringoxygen therapy, severe renal impairment [e.g. estimated creatinine clearance lessthan 30ml/min], history of major surgical resection involving the stomach or smallbowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chroniccondition resulting in baseline Grade 2 or higher diarrhea).

13. Concurrent active malignancy whose natural history or treatment has the potential tointerfere with safety or efficacy assessment of the investigational regimen.Patients with non-melanomatous skin cancer, superficial bladder cancer, cancer notneeding active therapy for at least 2 years, cancer for which the treatinginvestigator deems the subject to be in remission, or any prior malignancy that wastreated with curative intent (no evidence of disease for at least 3 years) arepermitted to enroll.