Phase 1/2 Trial to Evaluate Gedatolisib Plus Darolutamide Combo in mCRPC

Gedatolisib, an inhibitor targeting the PI3K/AKT/mTOR pathway, in combination with darolutamide, an androgen receptor antagonist, is being evaluated as a treatment option for metastatic castration-resistant prostate cancer (mCRPC).
In a phase 1/2 clinical trial, patients who had progressed on prior androgen receptor signaling inhibitors received once-weekly intravenous gedatolisib in doses of 120 mg or 180 mg combined with oral darolutamide twice daily. The treatment regimen follows a schedule of three weeks on therapy followed by one week off. Early data reveal a 6-month radiographic progression-free survival rate of 66%, suggesting encouraging preliminary efficacy in this difficult-to-treat population.

The mechanism of action of gedatolisib involves a comprehensive blockade of the PI3K/AKT/mTOR pathway by inhibiting all four class I PI3K isoforms and both mTOR complexes (mTORC1 and mTORC2). This dual inhibition aims to overcome resistance mechanisms arising from compensatory pathway activation often observed in prostate cancer. Darolutamide complements this by targeting androgen receptor signaling, a key driver of prostate cancer growth.

Safety findings are favorable, with no treatment discontinuations or dose reductions due to adverse events reported. Notably, no grade 3 hyperglycemia was observed, a common side effect of many PI3K inhibitors. Some patients experienced stomatitis, with approximately 10.5% having grade 2 or 3 events, which were manageable. The trial continues to explore optimal dosing levels with plans for expanded patient enrollment to confirm findings.

These results position the gedatolisib-darolutamide combination as a promising multitargeted approach in mCRPC, addressing both hormonal and growth signaling pathways simultaneously.

Source.

Clinical trial.