Neoadjuvant darolutamide and relugolix combination preceding radical prostatectomy for high risk localized and locally advanced prostate cancer: A phase I/Ib trial.

TPS433 Background: Intensive androgen blockade with combination novel hormonal agent (NHA) + androgen deprivation therapy (ADT) appears promising as neoadjuvant therapy for high-risk localized prostate cancer (PCa) undergoing radical prostatectomy (RP). An all-oral regimen combining relugolix and darolutamide may be feasible, convenient, efficacious and exhibit no significant drug-drug interactions as neoadjuvant therapy for high-risk localized PCa and may convert patients who were initially inoperable to operable. Additionally, the rapid reversibility of castration will allow the reliable determination of post-operative PSA nadir to inform tailored adjuvant therapy. Moreover, given the convenience, this regimen may constitute an excellent backbone to develop additional combinations in future. Hence, a rationale may be made to evaluate the combination of relugolix and darolutamide as neoadjuvant therapy for 12 weeks preceding RP for high-risk localized/locally advanced PCa. Methods: This is a Phase I/Ib non-randomized, uncontrolled, open-label clinical trial evaluating the primary objective of safety and feasibility of combination darolutamide (600 mg PO BID) and relugolix (360 mg on day 1, then 120 mg PO once daily) for 12 weeks as neoadjuvant therapy preceding RP which is to be performed ≥48 hours after and within 2 weeks after completion of neoadjuvant therapy. Patients included in this study must be a candidate for RP with stage cT2-4, N0-1, high risk (defined as 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); or ≥ 2 SB or TB with continuous GS ≥ 8, each with ≥ 80% involvement), histologically or cytologically confirmed adenocarcinoma of the prostate. The Phase I component will accrue 10 patients. If ≥7 patients complete neoadjuvant combination therapy followed by RP with no severe therapy-related adverse events for up to 4 weeks following RP, the regimen is considered feasible and accrual of 20 additional patients continues in the Phase Ib expansion component of the trial to achieve a total of 30 patients. Secondary objectives include clinical response, pathologic complete response with comparison with control matched untreated group that underwent upfront RP, rate of achieving undetectable PSA nadir and testosterone recovery to normal within 8 weeks after RP and post-operative complications. Pharmacokinetic studies are performed in the Phase I component. Blood, tumor and urine are stored for future correlative studies. The trial was activated in October 2024. Clinical trial information: NCT06631521 .