mCRPC in focus
Transcript: ARV-766: Initial results
Dr Neeraj Agarwal, Professor Karim Fizazi, Dr Bárbara Vieira Lima Aguiar Melão, and Professor Axel Merseburger
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.
So let's move on to the next promising target, which is PROTACs androgen receptor degraders. So Barbara, maybe you can tell us briefly about the initial results of a phase 1-2 study which used AR-V766, a new AR degrader. Thank you.
Of course. Thank you, Neeraj. Well, we know since studies in the 40s that prostate cancer is an androgen dependent malignancy, and then we target the AR signalling pathway. So doing so and especially now that we intensified this target AR signalling pathway inhibition and hormone sensitive castration, some tumours can develop resistance, and for many mechanisms, one of them is the mutations in the AR, which is found in 20 to 25% of our patients in mCRPC. So PROTAC androgen receptor degrader uses the body natural mechanisms to degrade protein, and targets clinically relevant mutations in the AR ligand binding domain, which is specifically associated to poor prognosis in these patients.
So this is a phase 1-2 trial, in part one, the phase 1, it was the phase 1 dose escalation. And actually patients enrolled had prior two systemic therapies, and the dose escalation and the endpoint was the interoperability of RP2D. And the second part, the phase 2 expansion, cohort expansion, patients enrolled, again heavily treated patients with metastatic mCRPC. And the pharmacogenetics of AR-V766 was dose dependent, they didn't reach maximum tolerated dose and there were no dose limiting toxicities different from the prior phase 1 trial that I presented. And actually this phase 2, the dose was randomised in 100 and 300 milligrammes orally QD, and the end points was the anti-tumour activity of AR-V766.
So there were more than 120 patients, and all of them have received prior ARPI. Half of them received prior chemotherapy, one quarter of them had visceral metastasis. And as I said, there were no dose limiting toxicities. But one third of the patients had grade three or four therapy related adverse events, most common were fatigue, nausea, diarrhoea. 77% of the patients have needed dose reductions, 8% of them needed discontinuations. And the results are very promising. 43% of the patients had 50% PSA decline, half of them had 30% PSA decline. And patients with soft tissue lesions, and this data is waiting for confirmation. But 30% had objective response rates in soft tissue lesions. So in conclusion, it's very well tolerated. Targeting these clinically relevant mutations in AR ligand binding domain with promising clinical activity.
Fantastic. Thank you so much, Barbara. So promising drug, targeting a well-known target, we have always known AR in prostate cancer. And we are really hoping that these results will pan out in larger trials and we'll have another treatment option for our patients in the near future.
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