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Responding to unmet needs for metastatic castration-resistant prostate cancer
mCRPC in focus

Transcript: ARV-766, a PROTAC AR degrader

Last updated:4th Jul 2024
Published:4th Jul 2024

Dr Alexander Chehrazi-Raffle

Interview recorded June 2024. All transcripts are created from interview footage and directly reflect the content of the interview at the time. The content is that of the speaker and is not adjusted by Medthority.

Approximately 20 to 25% of men with mCRPC will develop mutations in what's called the AR ligand-binding domain. Among these mutations are L702H, H875Y, and T878A. And so those are typically associated with a poor prognosis as they don't respond well to androgen receptor pathway inhibitors or ARPIs. ARV-766 is a novel proteolysis targeting chimaera or PROTAC for short, and that targets wild-type AR receptors and clinically relevant AR ligand-binding domain mutants, including the three I just mentioned. Unlike ARPIs, PROTAC's have been shown to exert what's called a bystander effect in that they target neighbouring proteins within the protein complex of the ligand-binding domain. So in the phase 1/2 study that reported out at ASCO, patients were first enrolled into a dose escalation phase and that established the recommended phase two dose of 100 milligrammes or 300 milligrammes daily.

Initially, the study was open to all comers, but it was subsequently amended to only patients with those three ligand-binding domain mutations. So among those patients, PSA 30 was 51% and PSA 50 was 43%. This was particularly impressive because these are heavily pretreated patients with up to seven, eight lines of therapy. So unconfirmed overall response rate was also a nice 30%, and the swimmer plot they depicted showed that about 25% of patients reached six months or more on therapy, suggesting that, for a subset, this is quite durable. So although these are admittedly quite early results, they nonetheless were very promising in this biomarker selected population. I also think these results underscore the need for practitioners to obtain somatic testing via tissue or liquid-based assays, as these tests can open the doors to more personalised treatments such as this one.

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