A phase 1/2, open-label, randomized, dose-finding and dose expansion study of gedatolisib in combination with darolutamide in metastatic castration-resistant prostate cancer (mCRPC).

TPS304 Background: Progression to mCRPC occurs in most patients (pts) treated with androgen receptor pathway inhibitors (ARPI) for advanced disease. Preclinical studies demonstrate that AR and PI3K-AKT-mTOR (PAM) pathways interact through reciprocal negative feedback, whereby inhibition of one pathway activates the other (Crumbaker et al. Cancers Basel 2017). Combination of a PAM inhibitor + ARPI may produce synergistic antitumor effects in mCRPC, including in pts with prior ARPI progression. Results of a randomized Phase (Ph) 2 trial showed improved median radiographic progression-free survival (rPFS) when samotolisib, a dual PI3K-mTOR inhibitor, was added to enzalutamide in pts with mCRPC that progressed on abiraterone (Sweeney et al. Clin Cancer Res 2022). Methods: This open-label, multicenter, Ph 1/2 study will evaluate the safety and efficacy of gedatolisib combined with darolutamide in mCRPC that has progressed on ARPI. Key inclusion criteria: men ≥ 18 years with progressive mCRPC on or after treatment with at least one next-generation ARPI (eg, abiraterone, enzalutamide, apalutamide, darolutamide); ECOG 0-1; measurable disease per RECIST 1.1/PCWG3. Key exclusion criteria: adenocarcinoma with a small cell component or with ≥10% neuroendocrine type cells; prior treatment with PI3K, AKT, or mTOR inhibitor; prior chemotherapy or radiopharmaceutical therapy for mCRPC; uncontrolled type 1/2 diabetes; or active brain or leptomeningeal metastases. In Ph 1, 38 pts will be randomized to one of two dose arms to evaluate dose limiting toxicities (DLTs). Gedatolisib will be administered once weekly for 3-weeks-on/1-week-off (intermittent): Arm 1 – 120 mg and Arm 2 – 180 mg, with darolutamide 600 mg orally administered twice daily. Upon completion of Arms 1 and 2, up to 3 additional dose escalation Arms and a Ph1b part were added to determine RP2D. New dose escalation arms use a non-randomized, 3+3 dose escalation design exploring gedatolisib intermittent Arm 3 (240 mg) and Arm 4 (300 mg), respectively plus darolutamide. An optional Arm 5 may subsequently explore weekly gedatolisib doses with darolutamide. The Phase 1b part will include up to 4 cohorts comparing up to 2 dose levels and schedules. In Ph 2, up to ~18 pts will be enrolled to achieve a total of ~30 pts at the RP2D and selected dosing schedule. Primary objectives for Ph1/1b are to assess the safety and tolerability of gedatolisib in combination with darolutamide, to compare the Bayesian-Optimal interval utility score between arms, and to determine the RP2D. Primary objectives for Ph 2 are to assess the antitumor activity of the combination as demonstrated by rPFS. This trial (NCT06190899) is currently open for enrollment across 13 sites in four countries: United States, Spain, France, and United Kingdom. Clinical trial information: NCT06190899 .