DASL-HiCaP Phase 3 Trial [2022]: Update David Wise MD
David Wise, MD Spoke with OncologyTube about the DASL-HiCaP (randomised) Phase 3 Trial
The DASL (DASL-HiCaP) (randomised phase 3 clinical trial) trial. It’s one of the key trials going on right now in the non-metastatic space. And we need a lot more innovation for non-metastatic prostate cancer (or very high risk cancer). Of course, patients with this non-metastatic cancer have a far longer life expectancy and do well.
But we still certainly need to do better. And I think that Darolutamide or NUBEQA as the brand name is certainly an agent well positioned to help patients do even better. So thalidomide is another example of an advanced androgen receptor-directed therapy similar to Enzalutamide and Apalutamide.
They are antiandrogens and more advanced than the first-generation versions like bicalutamide and flutamide. What sets apart Darolutamide (NEBEQA dasl hicap darolutamide augments (randomised phase 3 clinical trial)) is its thought that Darolutamide (NEBEQA dasl hicap darolutamide augments) has a lower blood-brain barrier penetration than, compared to Enzalutamide and Apalutamide. Of course, we know fatigue, cognitive impairment, and balance problems.
All presumably are neurologic toxicities from Enzalutamide, and Apalutamide is a major side effect that can affect some men. And the thought is that Thalidomide, based on some of the randomized data that’s emerged, looks to have at least primarily a lower rate of those side effects and a very promising effectiveness profile in its FDA-approved indications of non-metastatic hormone-resistant prostate cancer, and metastatic hormone-sensitive prostate cancer, where the effectiveness of Darolutamide (NUBEQA) looks very comparable to the other, key agents in the space.
And it became apparent then to try to develop this agent even further and help men with earlier non-metastatic hormone-sensitive prostate cancer do better. And so that sort of lays the foundation for this study in which men with a very high-risk disease that’s localized and either naive to any treatment or that recurs, despite radical prostatectomy with a rising PSA where the standard of care for both of those entities is combined treatment with ADT (androgen deprivation therapy) and radiation. Why not add Darolutamide (NUBEQA) to that doublet therapy and see if we can improve outcomes? That way, with the idea that hormone-resistant cells are likely there, or the predisposition to hormone resistance is there. And so, why not fully down-regulate the androgen receptor by combining ADT (androgen deprivation therapy) with Darolutamide?
What is the Standard of Care for Localised Very High-Risk Prostate Cancer?
The treatment approach to localized, very high-risk prostate cancer is quite complicated. There are multiple options available to patients. A radical prostatectomy is an available option for patients who are resectable, but for the vast majority of patients with very high-risk disease or metastasis (free survival) to the lymph nodes, the standard (therapy) of care is typically long-term ADT (androgen deprivation therapy) with external beam radiation therapy.
That was the standard (therapy) of care prior to the launch of the DASL (DASL-HiCaP randomised phase 3 clinical trial) trial, and the DASL (DASL-HiCaP) clinical trial simply asks for very high-risk patients or patients who are node positive, whether the addition of Darolutamide (NUBEQA dasl hicap darolutamide augments) it will lead to a significant delay and improvement in metastasis-free survival compared to patients who are getting the standard long term ADT (androgen deprivation therapy) plus radiation therapy.
The same can be said for the other arm of the clinical trial, who are patients that are progressed with a rising PSA after prostatectomy and have very high-risk features which, as the standard (therapy) of care based on the RTOG 9601, is to treat those patients with long term hormonal therapy.
We use ADT (androgen deprivation therapy), although that clinical trial did use high-dose Darolutamide (NEBEQA dasl hicap darolutamide augments) combined with radiation therapy. And similarly, DASL (DASL-HiCaP for high risk patients with prostate cancer) asks about the benefits of whether we should be adding Darolutamide (NUBEQA) to that doublet as well now. What’s emerged during the course of this DASL (DASL-HiCaP) trial are Abiraterone and the STAMPEDE data in which we now know that Abiraterone does prolong overall survival in the treatment-naive setting when added to ADT (androgen deprivation therapy) plus radiation therapy.
And so, I would argue that it is now an emerging standard (therapy) of care. However, that data was for the naive setting, and very few patients on that trial were in the post-prostatectomy, rising PSA setting. And so, I would argue that the DASL (DASL-HiCaP) trial will give us a critical data set for that patient population, where we don’t have a mature study that looks at the intensification of AR-directed therapy for patients with a rising PSA.
What are your hope for DASL Trial?
We’re hoping for a significant delay in the development of metastasis. What we’re hoping for is that we’re curing more men with localized, very high-risk diseases. I think that’s been the question of whether we can cure more men by hitting the AR harder with intensification, with a novel AR-directed therapy.
That’s really what we’re hoping for in this study. But what I would say is even short of a cure, if we’re able to significantly delay metastasis in this patient population with a manageable safety profile on the same excellent neurocognitive safety profile that we’ve seen with Darolutamide (NUBEQA) in the advanced disease setting, that would be certainly a success.
What were the specific inclusions and exclusions of the DASL-HiCaP trial?
This is largely a very high-risk (cancer) disease study or regionally metastatic study. So patients (with cancer of the prostate) cannot have distant metastases, but they must have pelvic lymph node metastasis. And this is on a scan, in the treatment-naive setting, or they have to have other very high-risk (cancer) disease features (very high risk features) in the post-prostatectomy cohort patients (with cancer of the prostate) who have pathologic lymph node metastasis that is lymph node metastasis that is visible on review of the surgical pathology that state does confer eligibility to the patient.
In addition, To other very high-risk (cancer) disease features (very high risk features), the trial’s primary endpoint is metastasis for survival because that has been validated by the Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) to be a surrogate of overall survival. And that has helped accelerate our clinical trials because we can get access to the critical endpoint earlier and make critical determinations about the effectiveness of agents way earlier than we’ve previously been able to. It’s a randomized trial (placebo controlled trial). Patients (with cancer of the prostate) are treated with 48 weeks of ADT (androgen deprivation therapy) in both arms and a standard radiation field in both arms.
There is a placebo-controlled trial in which patients (with cancer of the prostate) are treated with Darolutamide or placebo (controlled trial) on top of that standard hormonal therapy plus radiation therapy backbone.
Final Thoughts on the DASL-HiCaP Clinical Trial (placebo controlled trial)
I think we’ve learned from the metastatic prostate cancer treatment paradigm and from decades of research that our advanced AR targeted therapies are targeting a key resistance mechanism in prostate cancer. And that’s the case because our therapies that are life-prolonging in mCRPC (Metastatic Castration-Resistant Prostate Cancer) when we use them in hormone-sensitive, metastatic prostate cancer, we’ve seen an.
Further, increase in survival to a far greater degree than what we saw when we use them in men who are the most advanced in their disease with mCRPC (Metastatic Castration-Resistant Prostate Cancer). The question is, does that paradigm continue as we go earlier and earlier in the disease space? And I think it’s critical that we’re using agents that we think men are going to tolerate well.
And that tolerability question is going to loom large over these types of studies. But I think that we have agents that most men do tolerate well. Men are already treated with ADT (androgen deprivation therapy) for a long time. Who has high (risk cancer) or very high-risk prostate cancer? (very high risk features) And so when we know in the situation now where we know the science, AR is a critical target and that hormone-resistant cells.
If driven primarily through AR, the rationale is strong that we should try to target AR further to starve cancer from testosterone signaling. And that’s really how I explain it to patients (with cancer of the prostate). And so that sets us up for this study and by adding Darolutamide and multiple other trials in this space where we’re looking at novel AR-directed therapies to try to starve cancer fully.
Can we cure more men? And can we delay the development of metastatic disease in these men with advanced localized disease? And that’s really what we’re hoping for. This trial (placebo controlled trial) is being run around the world. We hope that accrue quickly. And then, we get the answer to this question as quickly as we can for our patients.
David Wise, MD, Ph.D. – Lutetium-177"“PSMA-617 [2022]: Update David Wise MD
https://oncologytube.com/video/41322
Professor Ray McDermott – SMO poster DASL-HiCaP: Darolutamide augments standard therapy for localized very high-risk cancer of the prostate (ANZUP1801)
https://oncologytube.com/v/39491
David Wise, MD, Ph.D. – About The Author, Credentials, and Affiliations
David R. Wise is an assistant professor in the Department of Medicine and the Department of Urology at NYU Langone’s Perlmutter Cancer Center focusing on clinical oncology. He holds a doctorate and a medical degree. Dr. Wise practices medicine in New York, New York, and specializes in clinical oncology and clinical trial or clinical trials. He has more than 11 years of expertise in the field of medicine. In 2011, he received his medical degree from the University of Pennsylvania School of Medicine. Appointments with his office can be made via telehealth.