mCRPC in focus
Transcript: Investigational treatments for mCRPC: Early findings
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 ARV-766, a new AR degrader.
Of course.
Thank you.
Thank you, Neeraj. Well, you know, since others in before is that prostate cancer is an androgen-dependent malignancy and then we target the AR signalling pathway. So doing so, and especially now that we are 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 mechanism 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, though, 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 safe and tolerability of RP2D. In the second part, the phase 2 expansion, a cohort expansion, patients enrolled, again, heavily treated patients with metastatic mCRPC, and the pharmacogenetics of ARV-766 was dose-dependent. They didn't reach maximum tolerate dose, and there were no dose-limiting toxicities different from the prior phase 1 trial that, phase that I presented. And, actually, this phase 2, the dose was randomising 100 and 300 milligramme orally, QD. And the added points was the anti-tumour activity of ARV-766.
So, there were more than 120 patients, and all of them have received prior ARPI, half of them received prior chemotherapy, 1/4 of them had visceral metastasis, and, as I said, there were no dose-limiting toxicities, but 1/3 of the patients had grade 3 or 4 therapy-related adverse events. Most common were fatigue, nausea, diarrhoea. 7% 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. Which I thought was quite exciting, and this was a phase 1 study of actinium-225-labeled antibody targeting human kallikrein-2 is a new target on metastatic prostate cancer or prostate cancer. So we have talked about PSMA being a target from Dr. Fizazi. Now we are talking about a new target, human kallikrein-2, on metastatic CRPC. So Barbara, would you like to discuss, tell us about the results of this phase 1 study presented by Dr. Mike Morris.
Absolutely, thank you, Neeraj. Well, since we have some treatment options in mCRPC that moved early on, we need more options, and I'm happy to present the novel agents of the new target, the human kallikrein-2, but so far, in prostate cancer, we just have one cell surface target, which is PSMA, and lutetium PSMA, as presented, is approved in mCRPC after aRP and taxane for now. And while JNJ-6420 is a radioligand that delivers alpha radiation targeting human kallikrein-2, and human kallikrein-2 is a cell surface antigen, highly expressed in prostate tissues and prostate cancer cells, and also, little or non-expressed in non-prostate tissues, so it's also very specific, and its expression is driven by AR signalling, and higher expression is correlated with increased cell proliferation in mCRPC, so, probably a very good target.
So this phase 1 trial presented by Michael Morris from Memorial, patients enrolled had at least one prior ARPI, chemotherapy was allowed, but no prior radioligands were allowed. Primary endpoint was recommended phase 2 dose, and safety, well, they started scheduling with dose escalation, and there were important therapy-related adverse events, persistent thrombocytopenia and two grade 5 events due to interstitial lung disease. So they moved to establish a dose cap of 500 microcuries, and the anti-tumour activity was maintained, however, still important treatment-related events that were not totally mitigated, so they moved to scheduling an adaptive dosing of 250 microcuries, wait for a biochemical relapse, and a recovery of platelets, and then re-dose with 150, respecting the dose cap of 500 microcuries, so it was adjusted for patients' individual response and tolerance. And then, the dose cap and the scheduling, the adaptive scheduling, they could mitigate persistent thrombocytopenia and also interstitial lung disease, which were dose-related, and interstitial lung disease only occurred with doses of 600 microcuries. So the population was heavily treated. Patients with mCRPC, half of them had two prior ARPIs, 2/3 had prior chemotherapy, and 1/3 had two prior, received two prior chemotherapies. So they also looked at response, anti-tumour activity, and it was very promising. 44% of the patients had PSA50 response, 9% of them, PSA90 response, and for patients with measurable disease, 18 had overall response rates, and about the duration, almost 1/3 have a response greater than six months, and Morris showed some patients that are on the trial and with durable response up to 27 months. So, in conclusion, it's a very promising radioligand, a new radioligand, with a very good target, and I'm looking forward to hear your thoughts. and especially Fizazi, which is very involved in radioligands.
Sure, you know, happy to. Thank you, Barbara, and happy to comment on that. Well, you know, first, I think, regardless of how we target it, a radioligand or something else, I think it's the first time we have a clear demonstration, clinical demonstration, that targeting kallikrein-2 can make a difference and can be active and efficacious in this disease. It's obviously not a new target. We know HK2 for two or three decades at least, and when, you know, when you think about it, it's actually bizarre that we never designed, or that the pharma industry never designed, drugs targeting HK2 because, you know, speaking about kallikrein, you know, the most famous kallikrein is actually PSA, which is HK3. The bad thing with PSA is that it's a secreted protein.
So if you're inventing a drug that targets PSA, it will go to your blood, but not to cancer cells, but HK2, in contrast to PSA, is actually, partially, a transmembrane protein and partially secreted as well. And it's highly, as you rightly said, it's highly expressed at the surface of cancer cells. So that's a quite important target, potentially. So, again, it's the first time it's being targeted with an agent, really active. We need to better figure out whether the expression of a protein makes a difference, yes or not, and when you think about it, in just less than a year, we saw two new targets being validated. STEAP1, which was shown to be targetable at ESMO last year, with clearly activity as well, and now HK2.
The question in the long term to me is whether we will target HK2 using actinium, which was done in this particular trial, or whether the antibody can be linked to something else. It can be an ADC, it can be also a bispecific strategy. And I know that all that is currently ongoing. So, but again, I think it's super important for us to see that, for the first time, the new target is validated. Perhaps in just, I don't know, three or five years from now, we will use a combo of PSMA targeting, HK2 targeting, and STEAP1 targeting together, and maybe AR targeting, who knows? But I think it's a very important signal for the future because it means that, very, very likely, these targets are here to stay, and we will probably use one weapon or another in our practise.
Such exciting times for our patients and for us who are practising medicine in prostate cancer. I agree with you. Thank you very much for such fantastic summary and analysis, your viewpoints on this trial.
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