Gedatolisib Shows Encouraging Early Efficacy in mCRPC and HER2+ mBC
Preliminary data highlights gedatolisib's potential in treating mCRPC and HER2+ mBC, showcasing promising efficacy and a favorable safety profile.
Preliminary clinical data for gedatolisib, a novel multi-target inhibitor of the PI3K/AKT/mTOR (PAM) pathway, indicate promising efficacy and a manageable safety profile in patients with metastatic castration-resistant prostate cancer (mCRPC) and HER2-positive metastatic breast cancer (HER2+ mBC). The findings, released by Celcuity Inc, suggest gedatolisib's comprehensive blockade of the PAM pathway may offer a beneficial therapeutic approach in these challenging oncology settings.
mCRPC: Gedatolisib Plus Darolutamide Demonstrates Favorable 6-Month rPFS
PC-3 human prostate cancer cells: © heitipaves - stock.adobe.com
In the phase 1 portion of an open-label, multicenter, phase 1/2 clinical trial (NCT06190899) evaluating gedatolisib in combination with darolutamide (Nubeqa), an approved androgen receptor inhibitor, 38 patients with mCRPC were randomized to receive darolutamide with either 120 mg or 180 mg of gedatolisib once weekly for 3 weeks on, 1 week off. Preliminary efficacy and safety analyses, with a data cut-off of May 30, 2025, from the combined arms revealed a 6-month radiographic progression-free survival (rPFS) rate of 66%. This figure compares favorably to published data for androgen receptor inhibitors alone in this patient population.
Safety analyses were also encouraging. No patients discontinued treatment due to a treatment-related adverse event (AE), and no dose reductions were required for either gedatolisib or darolutamide. Importantly, no grade 3 hyperglycemia was reported. Grade 2 to 3 stomatitis was observed in 4 (10.5%) patients, with 3 (7.9%) experiencing grade 2 and 1 (2.6%) experiencing grade 3.
Igor Gorbatchevsky, MD, chief medical officer of Celcuity, expressed optimism regarding the preliminary data. "The 66% 6-month rPFS rate for this novel combination therapy compares favorably to published data for androgen receptor inhibitors in this setting," he said in a press release.
Based on available pharmacokinetic (PK) data from other solid tumor trials suggesting a relationship between efficacy and dose, the clinical trial protocol has been amended. The phase 1 portion will now explore additional gedatolisib doses, with up to 6 patients planned for enrollment in each of 3 new arms.
Following phase 1 completion, up to 40 additional patients will be randomized into up to 4 phase 1b cohorts to determine the recommended phase 2 dose (RP2D). The subsequent phase 2 dose expansion study will enroll up to 18 additional patients, aiming for approximately 30 patients treated with the RP2D in combination with standard doses of darolutamide.
HER2+ Metastatic Breast Cancer: Encouraging ORR and Survival in Heavily Pretreated Patients
Breast cancer cells: © LASZLO- stock.adobe.com
In an investigator-sponsored phase 2 clinical trial (NCT03698383), gedatolisib in combination with trastuzumab-pkrb (Herzuma) was evaluated in 44 patients with HER2+/PIK3CA-mutated mBC. Notably, no stomatitis prophylaxis was administered in this trial. The patient cohort was heavily pretreated, with a median of 4 or more prior anti-HER2 therapies received in the metastatic setting; 86% of patients had received at least 3 prior anti-HER2 therapies. Data for this trial was cut off on February 10, 2025.
Key efficacy results, previously presented at the American Society of Clinical Oncology (ASCO) meeting in June 2025, demonstrated an objective response rate (ORR) of 43% among all enrolled patients. The median progression-free survival PFS was 6.0 months (95% CI, 5.0-7.7), and the median overall survival (OS) was 24.7 months (95% CI, 17.3 to not reached).
The safety profile in this cohort was also favorable, with no patients discontinuing gedatolisib due to a treatment-related AE. One (2.3%) patient experienced grade 3 hyperglycemia.
Gorbatchevsky commented on these findings, saying, "The 43% ORR reported in patients who received at least 3 prior lines of anti-HER2 treatment for their disease is very encouraging and compares favorably to published data for other available therapies in this group of patients." He emphasized the regimen's tolerability, noting that, "While additional clinical studies are needed, this data suggests gedatolisib in combination with HER2 targeted therapy may be an effective and well tolerated therapeutic option for patients with HER2+ mBC."
Gedatolisib's Differentiated Mechanism of Action
Gedatolisib is described as a potent, pan-PI3K and mTORC1/2 inhibitor designed to induce comprehensive blockade of the PAM pathway. This mechanism of action, addressing all 4 class I PI3K isoforms and both mTOR complexes, is presented as differentiated from other currently approved and investigational therapies that target PI3Kα, AKT, or mTORC1 alone or in combination.
The ongoing clinical development program for gedatolisib also includes a phase 3 clinical trial (VIKTORIA-1; NCT05501886) evaluating the drug in combination with fulvestrant (Faslodex) with or without palbociclib (Ibrance) in patients with hormone receptor-positive (HR+)/HER2-negative (HER2–) advanced breast cancer,2 and another phase 3 clinical trial (VIKTORIA-2; NCT06757634) investigating gedatolisib plus a CDK4/6 inhibitor and fulvestrant as first-line treatment for patients with HR+/HER2– advanced breast cancer.3
