Gedatolisib plus darolutamide shows preliminary activity in mCRPC

Gedatolisib plus darolutamide (Nubeqa) was associated with preliminary antitumor activity and a manageable safety profile in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with an androgen receptor pathway inhibitor (ARPI), according to phase 1b/2 findings presented at the 2026 European Society for Medical Oncology (ESMO) Congress in Madrid, Spain.¹

The findings, taken from the CELC-G-201 study (NCT06190899), provide an early assessment of combining inhibition of the PI3K/AKT/mTOR signaling pathway with androgen receptor inhibition in mCRPC.

Trial design and patient population

CELC-G-201 is a phase 1/2, open-label, dose-finding and dose-expansion study evaluating gedatolisib in combination with darolutamide in patients with mCRPC whose disease progressed following treatment with an androgen receptor pathway inhibitor (ARPI), or a PARP inhibitor if patients were BRCA-positive. Investigators enrolled patients through 13 sites across the United States, Spain, France, and the United Kingdom. To be eligible for enrollment, patients needed to have an ECOG Performance Status of 0 to 1, a life expectancy of at least 3 months, and adequate organ function.

The analysis presented at ESMO 2026 included 45 patients who were randomly assigned to receive darolutamide at 600 mg orally twice daily with one of 3 intravenous gedatolisib doses. Gedatolisib was administered at 120 mg (n = 19), 180 mg (n = 19), or 240 mg (n = 7) on days 1, 8, and 15 of each 28-day cycle, followed by 2 weeks off treatment.

The primary objectives of the dose-finding portion were to assess safety and tolerability and identify a recommended phase 2 dose. The phase 2 portion is intended to further evaluate safety and preliminary antitumor activity, including radiographic progression-free survival (rPFS), at the recommended phase 2 dose.

Radiographic progression-free survival and PSA responses

Among 22 patients with prior abiraterone (Erleada) exposure, median rPFS was 15.7 months (95% CI, 7.5 to NR), and the 6-month rPFS rate was 82.2% (95% CI, 54.3 to 93.9). Among 18 patients previously treated with enzalutamide (Xtandi), the median rPFS was 9.1 months (95% CI, 4.0 to 15.7), and the 6-month rPFS rate was 62.5% (95% CI, 34.0 to 81.5).

Further, among patients with prior exposure to both abiraterone and enzalutamide, the median rPFS was 10.4 months (95% CI, 7.5 to NR), and the 6-month rPFS rate was 72.9% (95% CI, 52.7 to 85.6).

Exploratory analyses also suggested antitumor activity independent of PTEN status. Among patients with prior abiraterone and enzalutamide exposure, median rPFS was 15.7 months (95% CI, 7.5 to NR) in the PTEN-intact subgroup and 9.1 months (95% CI, 1.9 to NR) in the PTEN-loss subgroup.

However, the authors noted that “The limited sample sizes and overlapping confidence intervals preclude definitive conclusions regarding differential treatment effect.”

Prostate-specific antigen (PSA) responses were also observed. Among patients previously exposed to both abiraterone or enzalutamide, PSA reductions of at least 50% from baseline occurred in 36%, 47%, and 67% of patients receiving gedatolisib at 120 mg, 180 mg, and 240 mg, respectively. PSA reductions of at least 90% were observed in 7%, 20%, and 33% of patients, respectively.

Safety findings

The combination was generally well tolerated across the 3 evaluated gedatolisib dose levels, according to the authors. Treatment-related adverse events (TRAEs) were reported in 95.6% of patients (43 of 45). Grade 1 or 2 TRAEs occurred in 75.6%, while grade 3 TRAEs occurred in 20.0%. No grade 4 or 5 TRAEs were reported.

One dose-limiting toxicity, grade 3 rash, was observed. Rash (n = 4) and pruritus (n = 2) were the only grade 3 TRAEs reported in more than 1 patient. No TRAEs led to treatment discontinuation or death.

According to the authors, these findings support continuation of the trial to the dose optimization portion and further evaluation of gedatolisib plus darolutamide in this setting.

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REFERENCE

1. Sharp A, de Bono K, Gonzalez BM, et al. 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). Presented at: 2026 European Society for Medical Oncology Congress. October 23-27, 2026. Madrid, Spain. Poster 2237P