ENV105 Phase 2 Trial for mCRPC: Can Prostate Cancer Be Made Sensitive to Hormone Therapy Again?

We already discussed ENV105(carotuximab) in a previous ProstateWarriors article, when the safety lead-in of its phase 2 trial in metastatic castration-resistant prostate cancer was completed. Since then, the programme has produced its first meaningful efficacy signal, making it worth revisiting.

ENV105 targets CD105, a protein that appears to become more active as prostate cancer develops resistance to androgen-receptor therapies. The strategy is unusual: instead of abandoning hormone therapy once it stops working, ENV105 is designed to block the resistance mechanism and make the tumour sensitive again. In the current phase 2 trial, ENV105 is combined with apalutamide in men with mCRPC who had already failed at least one previous androgen-receptor inhibitor.

The first interim efficacy analysis included 10 patients from the safety cohort. Two withdrew for reasons unrelated to treatment, leaving eight evaluable patients. Median progression-free survival was reported at more than 13 months, and five of the eight patients were still receiving treatment without progression at the time of analysis. In addition, 7 of 9 patients showed a PSA decline from baseline.

These numbers are intriguing because the trial was designed around a much more modest target. The investigators considered an improvement in median PFS from about 3.7 months to 6.7 months clinically meaningful; the early ENV105 plus apalutamide data have so far exceeded that benchmark. However, this remains a very small interim cohort, and the ongoing randomised trial will be needed to determine whether the benefit holds in a larger population and against apalutamide alone.

The concept is particularly interesting because resistance to androgen-receptor therapy does not always mean prostate cancer has completely stopped depending on the AR pathway. In some cases, the tumour may simply have developed protective mechanisms that allow it to survive despite continued AR blockade. If one of those mechanisms can be removed, an apparently “failed” therapy could potentially become effective again.

The idea has already shown an earlier signal. In a previous small study, combining ENV105 with an anti-androgen produced a 62% clinical benefit rate in resistant prostate cancer, supporting the hypothesis that CD105 blockade might restore sensitivity rather than act as a conventional anticancer drug on its own.

ENV105 is also being considered for a future combination study with radium-223 in metastatic prostate cancer involving bone, suggesting that CD105-targeting may have potential beyond AR-directed therapy alone.

Clinical trial.