Gedatolisib plus darolutamide shows encouraging activity in mCRPC

The combination of gedatolisib and darolutamide (Nubeqa) showed encouraging safety and preliminary efficacy in patients with metastatic castration-resistant prostate cancer (mCRPC), according to initial data from the phase 1 CELC-G-201 trial (NCT06190899).¹

There were no treatment discontinuations due to treatment-related adverse events.

According to Celcuity, “Gedatolisib is a multi-target inhibitor that addresses all 4 class I PI3K isoforms and the mTOR complexes mTORC1 and mTORC2 to induce comprehensive blockade of the PI3K/AKT/mTOR (“PAM”) pathway.”

In the phase 1 study, the combination demonstrated a 6-month radiographic progression-free survival (rPFS) of 66%.

Further, safety data showed no treatment discontinuations due to treatment-related adverse events, nor any dose reductions. Additionally, no grade 3 hyperglycemia was reported. Overall, 4 patients (10.5%) experienced grade 2 or 3 stomatitis, of which 3 (7.9%) were grade 2 and 1 (2.6%) was grade 3.

“We are very encouraged by this preliminary efficacy and safety data,” said Igor Gorbatchevsky, MD, Chief Medical Officer of Celcuity, in the news release.¹ “The 66% 6-month rPFS rate for this novel combination therapy compares favorably to published data for androgen receptor inhibitors in this setting.”

In total, the open-label phase 1 study enrolled 38 adult patients with mCRPC through clinical trial sites across the US, United Kingdom, France, and Spain.² To be eligible for enrollment, patients needed to have experienced progression following treatment with an androgen receptor signaling inhibitor. Patients also need to have an ECOG Performance Status of 0 or 1 and adequate bone marrow, hepatic, renal, and coagulation function.

For the study, participants were randomly assigned to receive 600 mg darolutamide twice daily in combination with either 120 mg gedatolisib (arm 1) or 180 mg gedatolisib (arm 2). All patients received prophylactic treatment for stomatitis.

Gorbatchevsky added in the news release,¹ “With no treatment-related discontinuations and less than 3% of patients experiencing grade 3 stomatitis, we believe it is important to explore additional dose options for gedatolisib. Available gedatolisib pharmacokinetic (PK) data from other clinical trials in solid tumors suggests a relationship between efficacy and dose levels. Since this preliminary data indicates that the optimal gedatolisib dose for patients with mCRPC may not yet have been reached, the company amended the clinical trial protocol to enable exploration of additional doses in the phase 1/1b portion of this clinical trial to determine the recommended phase 2 dose.”

With the amended protocol, the investigators will enroll up to 6 patients across 3 dosing arms for the phase 1 portion of the trial. Following completion of those cohorts, up to 40 additional patients will be enrolled in the phase 1b portion, assessing gedatolisib across 4 dosing cohorts to further determine the recommended phase 2 dose (RP2D).

Phase 2 of the trial will include approximately 30 patients, comprised of participants from the phase 1/1b portion of the study plus up to 18 additional patients, to assess the safety and efficacy of the RP2D of gedatolisib plus standard-dose darolutamide.

The primary outcome measures of the phase 1 portion include safety and tolerability of the combination as well as the identification of a RP2D. The primary outcome measure for phase 2 is rPFS at 6 months. Additional end points include rPFS at 9 and 12 months as well as overall survival at 18 and 24 months.

The company plans to share additional data from the phase 1 portion of the study at upcoming medical conferences this year.

Final completion of the phase 1/2 study is expected in November 2027.

REFERENCES

1. Celcuity reports clinical data from two early phase studies of gedatolisib. News release. Celcuity, Inc. June 30, 2025. Accessed July 1, 2025. https://www.globenewswire.com/news-release/2025/06/30/3107366/0/en/Celcuity-Reports-Clinical-Data-from-Two-Early-Phase-Studies-of-Gedatolisib.html

2. Gedatolisib in combination with darolutamide in metastatic castration-resistant prostate cancer. ClinicalTrials.gov. Last updated March 21, 2025. Accessed July 1, 2025. https://clinicaltrials.gov/study/NCT06190899