UPDATE: Gedatolisib Plus Darolutamide Shows Activity in mCRPC

Updated results from the phase 1/2 CELC-G-201 trial (we talked about it in this previous article) provide new evidence of antitumor activity for gedatolisib combined with darolutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with androgen receptor pathway inhibitors (ARPIs).

Gedatolisib inhibits the PI3K–AKT–mTOR signaling pathway, which can contribute to resistance to hormonal therapies. Combining it with darolutamide aims to block two interconnected pathways involved in prostate cancer growth and treatment resistance.

The updated analysis included 45 patients receiving three different doses of gedatolisib alongside standard-dose darolutamide. Approximately 42% had received at least two previous treatment lines, and 24% had previously received docetaxel.

A confirmed PSA reduction of at least 50% (PSA50) was observed in 26.7% of patients, increasing to 40.9% among those previously treated with abiraterone.

Median progression-free survival (PFS) was 9.1 months in the overall population and 15.7 months in the subgroup with prior abiraterone exposure. Median follow-up was 7.7 months.

The safety profile remained manageable in this preliminary analysis. Treatment-related grade 3 adverse events occurred in 16% of patients, most frequently rash. One dose-limiting toxicity was reported at the highest dose level. No grade 4 treatment-related adverse events, treatment-related discontinuations, or deaths were reported.

These findings suggest that combining PI3K–AKT–mTOR inhibition with androgen receptor blockade may retain activity after progression on previous hormonal treatments.

However, the study remains an early-phase, non-randomized trial without a control group. The abiraterone subgroup was relatively small, follow-up was limited, and the apparent differences between subgroups cannot establish greater treatment sensitivity. Longer follow-up and controlled studies will be needed to confirm the durability and clinical significance of these responses.

Source.