Dual targeting of PAM and AR pathways yields encouraging results in mCRPC

The combination of gedatolisib and darolutamide (Nubeqa) demonstrated promising safety and preliminary efficacy in patients with metastatic castration-resistant prostate cancer (mCRPC), according to data from a phase 1 trial (NCT06190899) presented at the 2025 European Society for Medical Oncology (ESMO) Congress in Berlin, Germany.¹

Gedatolisib is a “pan-PI3K, mTORC1/2 inhibitor that comprehensively blockades the PAM pathway,” according to the authors. The investigators hypothesized that combining a PAM inhibitor with an androgen receptor pathway inhibitor (ARPI) such as darolutamide may induce a synergistic anti-tumor effect in this patient population.

In a recent interview with Urology Times®, presenting author Alice Bernard-Tessier, MD, a medical oncologist at Gustave Roussy, France, further explained the rationale for this approach and touched on the preliminary findings from the trial.

In total, the study included 38 patients who received gedatolisib at 120 mg (arm 1; n = 19) or 180 mg (arm 2; n = 19) in combination with 600 mg darolutamide daily. Patients were enrolled across clinical trial sites in the US, France, Spain, and the UK.² Key end points include safety; determination of a recommended phase 2 dose; pharmacokinetics; radiographic progression-free survival (rPFS) at 6, 9, and 12 months; overall response rate; and overall survival.

Early results showed that the combination was well-tolerated, with no dose-limiting toxicities nor grade 4/5 treatment-related adverse events reported. The study remains ongoing to assess higher doses of gedatolisib in arms 3 (240 mg gedatolisib) and 4 (300 mg), along with optional weekly dosing in arm 5 (dose to be determined).

Urology Times: Could you describe the background/rationale for this study?

Bernard-Tessier: Gedatolisib is a PI3K/mTOR inhibitor of [the] PAM [pathway]. Gedatolisib was tested in this phase 1 trial in combination with darolutamide. Given the cross activation of the PI3K pathway and the AR pathway, it makes sense to target both these pathways together.

We've seen impressive results in breast cancer with the combination of endocrine therapy and this drug. So, we know that when we target AR, we’re activating the AKT pathway, and we know that AKT pathway is highly activated as a result of the resistance to ARPI. So, targeting both the PIK3/AKT/mTOR pathway and AR pathway makes sense together.

Urology Times: What were the key findings from this study?

Bernard-Tessier: This phase 1 trial is interesting, because it included patients who experienced disease progression with 1 ARPI before taxane-based chemotherapy. The combination was tested at 2 dose levels: 120 mg and 180 mg.

The key finding is, first, there were no new safety signals compared to what we observed in breast cancer. We didn't see any grade 3 hyperglycemia. Regarding efficacy, we can see that there is an impressive rPFS, from my perspective, compared with the ARPI historical progression-free survival data. Overall, the rPFS was 7 months in the 180-mg arm and 9.5 months in the 120-mg arm.

Urology Times: What are the next steps that are planned for this trial? What questions will the next phase of study try to answer?

Bernard-Tessier: We are still finding the best dose for the combination. We haven't explored all the doses, so we are still trying to see if increasing the dose can induce more efficacy and prolonged response without any grade 3 toxicities. The key questions are: To what extent can we safely escalate the dose, how can we further enhance this crossover activation, and where will this drug best fit in the treatment landscape?

REFERENCES

1. Bernard-Tessier A, Piulats JM, Esteban-Villarrubia J, et al. Phase I/II study of gedatolisib in combination with darolutamide in metastatic castration-resistant prostate cancer (mCRPC). Presented at: European Society for Medical Oncology Congress. October 17-21, 2025. Berlin, Germany. Abstract 2445P. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2025_abstracts/2445P.html.pdf

2. Gedatolisib in combination with darolutamide in metastatic castration-resistant prostate cancer. ClinicalTrails.gov. Last updated March 21, 2025. Accessed November 12, 2025. https://clinicaltrials.gov/study/NCT06190899