ARV-766 well tolerated and shows promising clinical activity in metastatic castration-resistant prostate cancer

Prof Daniel Petrylak - Yale School of Medicine, New Haven, USA

The body has a natural way of degrading proteins and as our proteins age we want to replace them with new, fresh proteins and the ubiquitin ligase pathway is one way in which our body will get rid of proteins within the cell and recycle them. So a PROTAC is a drug that binds to a protein and basically flags it such that this pathway will recognise it. ARV-766 is a PROTAC that binds to the androgen receptor and labels that as being ready for disposal. One PROTAC can take out as many as 400 androgen receptor molecules so this is a way that we can control patients or cause cell death in patients who have resistant prostate cancer. This has been shown in the laboratory. ARV-766 binds not only to wildtype androgen receptor but mutations of what’s called a ligand binding domain, which is the front portion of the androgen receptor molecule where testosterone or other ligands bind and therefore activate it.

The purpose of this trial was to evaluate ARV-766 in those patients who had previously been treated with chemotherapy, and they could receive up to two prior chemotherapies, or next generation hormones, they could receive up to three of those, and to determine whether we could see any effectiveness and also, of course, safety.

What we found was that patients who received ARV-766 had a 43% rate of a 50% PSA reduction. Those patients who had measurable soft tissue lesions had a 30% rate of reduction by RECIST criteria. So there is activity of this particular drug in this group of patients.

Of course, the question is safety and the majority of side effects that we see were nausea and fatigue. We did have three toxic deaths on the trial, they were deemed to be unrelated to the drug so disease progression, as well as other causes, were seen. So the drug is relatively safe and it’s also effective.

Our plan is to move this drug into phase III studies. It has demonstrated activity in castrate resistant prostate cancer as well as an acceptable safety profile.