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Zach Klaassen: Hi, my name is Dr. Zach Klaassen, and I'm a urological oncologist at the Georgia Cancer Center in Augusta, Georgia. We're here in San Francisco at the GU ASCO 2024 annual meeting, and I'm joined by Dr. Andrew Laccetti, a medical oncologist, GU medical oncologist, at Memorial Sloan Kettering Cancer Center in New York. Thanks so much for joining us today.

Andrew Laccetti: Thanks. Happy to be here.

Zach Klaassen: So we're going to talk about a trial in progress, which is really exciting because it's a great trial design, but it's also a very hot area. We're talking about ARAMON today, which is going to be looking at enzalutamide and darolutamide and their effect on testosterone levels in patients with high-risk nonmetastatic hormone-sensitive prostate cancer. So as I mentioned, this is hot. We've had EMBARK, we have a lot of stuff coming down the pipeline. What are your thoughts on this disease space and how this trial fits into it?

Andrew Laccetti: Yeah, I'll recapitulate that thought. It's a very interesting area, and an area where we've had a lot of movement, both for castration-sensitive and castration-resistant formulations of the biochemically relapsed space. So a critical element that really needs to be considered for this patient population is the fact that men with biochemically relapsed prostate cancer live for a long time.

Zach Klaassen: Right.

Andrew Laccetti: And the current protocol and systems by which we treat men mean they're on treatment for a long time as well.

Zach Klaassen: Right.

Andrew Laccetti: We've leveraged the opportunity to use intermittent hormonal therapy in the biochemically relapsed space, but this is still presenting significant symptoms for many men for the durations that they're on treatment, and for the durations where they're off treatment and we're awaiting testosterone recovery.

Zach Klaassen: Yes.

Andrew Laccetti: So a critical area of unmet need is the development of treatments that not only care for men better, from a cancer outcomes perspective in this setting, but also create a means by which we can limit side effects, toxicity, and improve the quality of life.

Historically, we've looked at strategies using first-generation antiandrogens drugs, like Casodex, as a non-castrating means to try and help accommodate side effects a little better.

Zach Klaassen: Right.

Andrew Laccetti: But in the contemporary era, where we have these novel agents, enzalutamide, apalutamide, darolutamide, the question is left to be asked whether or not we can do better?

Zach Klaassen: Right.

Andrew Laccetti: So can we treat cancer better with these potent agents? And can we create treatment programs that patients are able to better tolerate? So the ARAMON trial is asking that question, in a way, for darolutamide as monotherapy. We are specifically accruing men with biochemically relapsed cancer, so after prostatectomy with salvage radiation or primary radiotherapy; and then administering darolutamide as monotherapy, primarily focusing on its impact on testosterone.

Zach Klaassen: And when we look at this space, we talked about EMBARK last year, a big trial coming out, and we have ARASTEP that's accruing well. And hopefully, we'll have data soon, which is basically that darolutamide therapy, with the caveat of PSMA PET in the trial design. So if we're looking at ARAMON, how does it complement ARASTEP?

Andrew Laccetti: Yeah. ARAMON and ARASTEP are very well complemented. So as you mentioned, ARASTEP is looking at darolutamide in combination with ADT, compared to ADT alone, in the biochemically relapsed population of patients. Again, with the caveat that it allows for, I believe, fewer than five PSMA avid lesions. So we're essentially performing an EMBARK-like study with darolutamide but focusing on the ADT versus ADT and ARPI combination.

Zach Klaassen: Right.

Andrew Laccetti: With ARAMON, we're layering in the third arm that was represented in EMBARK with the enzalutamide monotherapy.

Zach Klaassen: Right.

Andrew Laccetti: So here, we'll have a data representation for darolutamide monotherapy, which will really complement ARASTEP well, providing an EMBARK-like data set, putting the two together.

Zach Klaassen: It's interesting because, as you mentioned, the quality of life for these patients is important, but also, we know that these patients with really rapid doubling times do have a mortality risk. So if we can take these two trials, let's say we're sitting here in 12 months and we've got data, it's going to be really interesting how we start to parse these together. I mean, it's going to be fun to see what T levels are and start to compare because we're going to have a lot of data to look at.

Andrew Laccetti: Yeah. And no, you hit upon a critical point. So the primary endpoint of this trial is actually the change in testosterone three months into the trial.

Zach Klaassen: Right.

Andrew Laccetti: So again, men all have biochemically relapsed cancer. We are allowing for some PSMA-positive disease, with fewer than five PSMA avid bone lesions, and men cannot have received any more than six months of ADT previously.

Zach Klaassen: Right.

Andrew Laccetti: So we're really trying to hone in on men that then haven't been heavily pretreated in that way.

So the study, unlike most others, is leveraging testosterone level as an endpoint.

Zach Klaassen: Right.

Andrew Laccetti: Under the hypothesis that as a drug, darolutamide is expected to penetrate the blood-brain barrier less. And under that theory, with less blood-brain barrier penetration, we anticipate a lesser degree of testosterone surge, through negative feedback on the GNRH axis.

So EMBARK has been studied; it studied enzalutamide. There are trials looking at apalutamide as monotherapy. And we know with Casodex, testosterone surge is a very critical issue that provokes some side effects with some of these monotherapy strategies, namely gynecomastia, breast tenderness, and other sexual side effects like low libido.

So there's a line of thought that if we're able to leverage this pharmacokinetic nuance of darolutamide, side effects in certain capacities may just be better.

Zach Klaassen: Sure.

Andrew Laccetti: So we will be doing in-depth assessments of adverse events, toxicity, quality of life, but the primary endpoint is being set at testosterone surge to really intently look at the biological effect of the drug.

Zach Klaassen: That's a great explanation. So where does the trial stand in terms of recruitment? What's the goal? And maybe we can start to see some results.

Andrew Laccetti: So a little bit more on the design of this study.

Zach Klaassen: Sure.

Andrew Laccetti: This is a Phase II trial that's built with a single arm lead-in. So men will all receive darolutamide, 600 milligrams twice a day, as monotherapy for a 52-week duration. We're targeting around 25 patients for that lead-in. And then, once the 25 patients have been accrued, and that three-month primary endpoint testosterone level is assessed, then we'll decide as to whether or not we'll move forward to a randomized component. That'll be comparing darolutamide and enzalutamide monotherapy. Again, positioning testosterone as the primary endpoint, but layering in a variety of other secondary endpoints.

Zach Klaassen: I see.

Andrew Laccetti: So we've completed enrollment into the lead-in phase.

Zach Klaassen: Excellent.

Andrew Laccetti: And we're awaiting data maturation, so we're eager to evaluate that data and decide on next steps.

Zach Klaassen: That's great. Anything we haven't hit on for ARAMON that you want to discuss and any take-home messages?

Andrew Laccetti: ARAMON is a very timely study, in that we're looking at a very patient-centered endpoint for the tolerability of therapy, looking at darolutamide as monotherapy.

Zach Klaassen: Right.

Andrew Laccetti: We are getting at that information through testosterone levels, which are inherently associated with some side effects we see with anti-androgen monotherapy strategies. Particularly in light of EMBARK, which was recently published and led to the FDA approval of enzalutamide as monotherapy. An in-depth understanding of other second-generation, or androgen receptor pathway inhibitors will really be critical for best drug selection and the creation of treatment strategies that patients tolerate best.

Zach Klaassen: That's great. Thanks so much for your time during a busy meeting, and we appreciate your expertise today.

Andrew Laccetti: Thanks so much.

Zach Klaassen: Thanks.