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Alicia Morgans: Hi, this is Alicia Morgans, GU Medical Oncologist and Associate Professor of Medicine at Northwestern University in Chicago, Illinois. And I am so excited to have here with me today a friend and colleague, Dr. Christopher Sweeney, who is a Professor of Medicine at Harvard, as well as a GU Medical Oncologist at the Dana-Farber Cancer Institute. Thank you so much for being here with me today, Chris.

Christopher Sweeney: It's my honor to be here today.

Alicia Morgans: Wonderful. Chris, I wanted to talk with you about an amazing effort that you are doing to try to help an urgent unmet need in men with prostate cancer, really those patients who have high-risk disease after their initial treatment. Can you tell us what is the urgent unmet need in this population and how did you and the team seek to conquer it?

Christopher Sweeney: So evidenced by the fact that the study chair on this paper is, this protocol, is Tamim Niazi from the Canadian Cancer Trials Group. Both he and I, and obviously, both groups between ANZUP, myself, Tamim, Canadian Cancer Trials Group, all realized that there is a patient population despite having a benefit with adding hormones to radiation or radiation to hormones. There's still patients who have a rapid progression. And we need to do clinical trials in that space. And that space is either in patients who have a very high-risk features and being treated with radiation as their primary modality or patients who've had surgery, and have a rising PSA, and have high-risk features after surgery. 

So this study is called "DASL-HiCaP: Darolutamide Augments Standard Therapy for Localized Very High-Risk Prostate Cancer." And we've really honed in on identifying patients who have 35% metastasis-free survival at five years, maybe a number of those patients will have either died of prostate cancer or another condition or have metastasis. And we kept showing that [inaudible] is a surrogate for poor overall survival. So we've really honed in on those patients with the eligibility criteria.

Alicia Morgans: So really you've identified a high-risk localized patient population who's undergoing primary therapy, but still has high-risk disease, very high-risk of having metastatic disease or dying from their cancer. And you've designed a study to address that and try to mitigate that risk.

Christopher Sweeney: Absolutely, and what we know is that we have had substantial benefits with potent AR inhibition with enzalutamide, apalutamide, and darolutamide in castration-resistant disease, be it evident on a conventional scan or in the M0 CRPC space. And also with enzalutamide and apalutamide in hormone-sensitive metastatic disease. So if we see a major benefit in that setting, will we be able to actually stop patients having metastatic disease after they've had their primary treatment? So, prevent the emergence of micrometastatic disease and increase the cure rate by decreasing the relapse rate by bringing therapy that is active in advanced-stage disease to the adjuvant micrometastatic setting.

Alicia Morgans: Great, so exactly what is this trial? It sounds like you're enrolling high-risk patients and what's the randomization?

Christopher Sweeney: So the randomization is for patients who would be treated with two years of hormonal therapy, with radiation, with their prostate intact, or patients who have a rising PSA after prostatectomy and have high-risk features such as lymph node-positive disease at the prostatectomy, and where you would be treating them with two years of hormonal therapy in the adjuvant setting and giving some salvage radiation.

Alicia Morgans: Great, and you're randomizing them to receive darolutamide or placebo?

Christopher Sweeney: So the standard arm will get just the hormonal therapy alone, plus the radiation. And half the patients will get randomized to placebo, and the other half will get randomized to darolutamide. They're very potent and well-tolerated androgen receptor inhibitor. And the main thing to note is that in the adjuvant setting where patients do not have any cancer and therefore no cancer symptoms, we need a well-tolerated therapy, which darolutamide is.

Alicia Morgans: Absolutely, it did have a really favorable safety profile and seemed to have a very tolerable profile, even from a patient-reported outcome perspective, which is really critical. So what are the endpoints? What's your primary endpoint that you're looking for to understand if these trials worked or not?

Christopher Sweeney: So we have looked to use metastasis-free survival, which is metastatic disease seen on a conventional CAT scan or a bone scan or death from any cause. And the reason we use that endpoint is that with the ASCaP working group, we've shown that if one can decrease the chance of the metastasis, in other words, increase the chance that the patient will get to five, eight years without a metastatic event, have a better metastasis-free survival, that improves the chances of an overall survival signal as well.

So if we can decrease the early event of metastatic disease, we can increase the overall survival of these patients with the use of this agent for two years at the time that they are being treated for their localized disease. So the primary endpoint is metastasis-free survival, as a surrogate for overall survival. For it to be a surrogate and have a meaningful endpoint, we actually have to see a 40% improvement in the metastasis-free survival from the ADT radiation alone to the ADT radiation plus darolutamide.

Alicia Morgans: I agree. That's really important, so that we're not just finding incremental change that's not worth the duration of this daily treatment. Now, as you were thinking about this trial, this is definitely going to need to enroll many patients, I assume, in the hundreds, if not the low thousands. And it's important, I think, to surely cast a wide net in terms of making sure you can get all those patients enrolled and do so in a timely fashion. You've had great luck with the ANZUP group in terms of collaborating and making a global team who can really answer some of these big questions, as you and the team did with the ENZAMET trial. You are again working with the ANZUP team to make this a truly global effort, aren't you?

Christopher Sweeney: For sure, so you're absolutely right. It is an 1100 patient study. It is an investigator-sponsored study. Namely, we, the investigators have sourced funding from Bayer who has been a great collaborator. And they have given us permission to run the study with their drug supply. And we, as a collaboration between the ANZUP Group based in Australia with the Clinical Trial Center as the coordinating center. And then we've brought in collaborations from Cancer Trials Ireland for recruitments from the UK and Ireland, and the Canadian Cancer Trials Group. And we're working to get the Prostate Cancer Clinical Trials Consortium to be the regional coordinating center in the United States, with me being the lead investigator with my position at Dana-Farber Cancer Institute and having a collaboration between Dana-Farber and the Prostate Cancer Clinical Trials Group.

That's not in place yet, but we're actively working our way through the logistics of that. So it's a very big undertaking, but what is fantastic is that we do have a track record. We were able to recruit and complete the ENZAMET study in metastatic hormone-sensitive prostate cancer. And within a few years, we're able to get a survival signal and present the results and get a publication showing the survival benefit of enzalutamide hormone-sensitive with this collaboration. And also we've completed a high-risk patient population just with radiation alone and not as high-risk as the DASL study with the ENZARAD study.

But as you can imagine, it is an incredible collaboration. And getting everyone on board, and putting the oars in the water, and rowing in the same direction has been an incredible effort that we've been able to get this activated globally already. So the study was actually activated in February 2020 in Australia with some amazing diligence. The issue was becoming quite problematic in the COVID era. And we have been able to start to get patients accrued to the study, because we were very diligent and very deliberate, and in no ways were we cavalier about trying to accrue patients to a study when the COVID pandemic was rearing its ugly head.

Alicia Morgans: So how has COVID really impacted the recruitment and the ability to get things off the ground or maybe it hasn't? What have you been seeing?

Christopher Sweeney: What we did when the lockdown started, we put a pause on everything. And got every regional coordinating center to give us feedback from around the globe, and also coordinate with Bayer and their impressions. And we would recognize that these are patients who needed active cancer therapy. If we let them go, they could well become metastatic and incurable, and therefore, we had to really push on. We also recognized that the treatment burden, with the addition of darolutamide to the standard treatment does not increase immunosuppression.

So the one risk would be the study protocol putting patients at risk if there was excess clinic visits. So what we've been able to institute is in telemedicine, where appropriate, and transportation of drugs to the patients when needed to avoid clinic visits and maximize social isolation. As a fellow ECOG member, I have also been following your great perseverance and diligence in getting the ERADICATE trial open. And I think it's worth highlighting how ERADICATE, that you're leading through the ECOG-ACRIN effort complements and does not compete with DASL-HiCaP.

Alicia Morgans: Sure, and thank you so much for your kind words. ERADICATE has truly been a labor of love over many years, but we're excited to get it off the ground. This is for patients who have undergone prostatectomy and have high-risk features clinically. And when they undergo a Decipher test, have a Decipher score that is greater than or equal to 0.6, which puts them in a high-risk patient population group. Those patients can enroll in ERADICATE and are randomized to treatment with darolutamide and ADT for a year versus ADT alone. But as you said, this population, though also high-risk, similar to DASL-HiCaP is a population that cannot have lymph nodes that have been involved. And so that would be an exclusion criteria for ERADICATE, and they also have to have an undetectable PSA by the standard assay, not by the ultra-sensitive assay. So in this setting, we see the DASL-HiCaP also requires a detectable and potentially rising PSA, is that right?

Christopher Sweeney: Correct, and it has to be within 12 months of the surgery, either persistent or within 12 months of the surgery, and has to be above 0.1.

Alicia Morgans: Yes, so very similar, but I think very clearly different in many ways. But what this does speak to is that if you have these patients who are high-risk after prostatectomy, there is probably an option for them, in terms of getting them additional therapy that may help prevent metastasis, and hopefully cure more men. So make sure that you do check out clinicaltrials.gov. And again, we'll put the link so that you can make sure that you can find the DASL-HiCaP study. Do consider it when it is open in an area near you. I think it will be great for your patients to consider enrolling. And thank you so much, Dr. Sweeney, for lending your time and expertise on this truly monumental global effort to cure more men with high-risk locally advanced prostate cancer. Thank you.

Christopher Sweeney: And together we will dazzle as we aim to eradicate prostate cancer.

Alicia Morgans: I love it. Thank you.