Comeback from long-course ADT with relugolix (rel) and darolutamide (daro) in hormone-sensitive prostate cancer (PC) (CLEARED).

5083 Background: The oral luteinizing hormone releasing hormone antagonist rel and androgen receptor pathway inhibitor (ARPI) daro are approved for treatment of advanced PC but the combination has not been prospectively investigated, and kinetics of testosterone (T) recovery after 2 years of rel have not been reported. Here we report pharmacokinetics (PK) as well as initial safety and reduction in T and PSA from a phase 2 trial of rel plus daro in high risk localized (HRL), lymph node-positive (N+) or low volume metastatic (LV) PC. Methods: Eligible patients (pts) had PSA > 0.02 ng/ml, T ≥ lower limit of normal (LLN) and were planned for 2 years of ADT+ARPI for HRL, N+ or LV PC. Prior ADT±ARPI was permitted if T recovered to ≥ LLN, but pts with high volume metastatic PC, prior PSA rise with castrate T, or on medications with significant predicted drug-drug interactions with rel or daro were excluded. Pts received rel 360 mg ×1 on day 1 (D1) followed by 120 mg QD and daro 600 mg BID starting on D1, and elected for PK sampling at 0h, 2h, 4h, 8h on D1 (cohort 1) or pre-dose on D1, 2, 8 and 29 (cohort 2). Radiation therapy to local and/or metastatic sites was delivered per standard of care. Pts receive up to 26 28-day treatment cycles with PSA/T monitoring every 3 months (mo) until 18 mo after end-of-treatment (EOT). The primary endpoints are rate of T recovery to > LLN by 18 mo after EOT and safety/adverse events (AEs). Secondary endpoints include PK, rate of treatment discontinuation, and pt-reported outcomes. Results: 33 pts enrolled: 8 with HRL, 11 with N+ and 14 with LV PC. 21 chose cohort 1 and 12 chose cohort 2. Single dose maximum concentrations (C max ) on D1 for rel and daro, and D29 pre-dose trough level (C trough ) for rel were similar to historical monotherapy comparators (comp) with geometric mean ratios (GMR) between 0.80-1.25 (Table), while D8 C trough for daro was slightly outside this range. By cycle 7 (C7) D1, 15 pts experienced Grade ≥3 AEs: 12 lymphopenia (3 possibly related to daro), with the remainder not treatment-related. 0 pts discontinued rel or daro; 3 dose-reduced daro. 33/33 (100%) pts achieved castrate T < 50 ng/dl and 32/33 (97%) achieved profound castrate T < 20 ng/dl (1 with T 24 ng/dl on C7 D1). PSA decline of ≥50% was achieved in 33/33 (100%) and decline ≥90% in 32/33 (97%) by C7 D1. Conclusions: The combination of rel and daro was safe and well-tolerated during the 1 st 6 treatment cycles, with PK parameters similar to historical monotherapy comparators. Appropriate initial T and PSA reduction were observed, and pts will be followed after EOT for the primary endpoint of T recovery (NCT06463457). Clinical trial information: NCT06463457 . PK for rel and daro. Geometric Mean Coefficient of variation (%) GMR rel D1 C max (N=19) [comp] 141.5 ng/ml [125] 145.2% [220%] 1.13 rel D29 C trough (N=11) [comp] 6.34 ng/ml [7.54] 62.6% [91.9%] 0.84 daro D1 C max (N=18) [comp] 2.10 µg/ml [1.77] 29.0% [26.4%] 1.19 daro D8 C trough (N=11) [comp] 2.52 µg/ml [1.82] 24.7% [32.8%] 1.38