New Trial for AMO959 and Pluvicto and ARSI Combo

The ongoing phase Ib/II trial investigating the combination of AMO959, Pluvicto(lutetium-177 vipivotide tetraxetan, also known as AAA617 or 177Lu-PSMA-617), and androgen receptor pathway inhibitors (ARPIs) in metastatic castration-resistant prostate cancer (mCRPC) explores a novel approach targeting disease through multiple pathways. AMO959 is a direct activator of AMPK, a key metabolic regulator that can disrupt cancer cell metabolism and inhibit androgen receptor function. Pluvicto,, a radioligand therapy targeting PSMA-positive prostate cancer cells, delivers beta radiation precisely to the tumor, complementing the hormonal blockade provided by standard ARPIs such as abiraterone or enzalutamide.

The trial’s rationale is based on combining these mechanisms to address resistance in mCRPC. AMPK activation may interfere with metabolic and proliferative pathways cancer cells depend on, while Pluvicto® exploits PSMA expression for targeted radiation treatment. The ARPIs maintain continued suppression of androgen receptor signaling.

Participants receive cycles with Pluvicto® given on day 1, followed by AMO959 twice daily for two weeks, alongside daily oral ARPI. Dose escalation in phase Ib seeks to determine the safe and tolerated dose of AMO959 in combination, with a phase II expansion to evaluate efficacy.

While Pluvicto has demonstrated efficacy in large phase III trials like VISION and PSMAfore by improving progression-free survival and overall survival, there are no published preliminary clinical results yet from combining it with AMO959. The current study is mainly focused on safety, tolerability, pharmacokinetics, and early signs of activity.

This approach represents an investigation into how metabolic targeting with AMPK activation may enhance the effect of established radioligand therapy and hormonal treatments, aiming to improve outcomes for patients with PSMA-positive mCRPC who have limited options after progression on prior ARPIs.

Clinical trial.