Darolutamide Monotherapy in Prostate Cancer: A Phase II Trial Overview - Xin Gao
February 26, 2025
Alicia Morgans is joined by Xin Gao to discuss the ARAMON study. This single-arm phase II trial evaluates darolutamide monotherapy without ADT in biochemically recurrent prostate cancer patients. The study finds darolutamide increases serum testosterone by only 53.5% at 12 weeks, considerably lower than the 114-134% increases seen with enzalutamide and apalutamide monotherapy. This likely results from darolutamide's unique structure and reduced blood-brain barrier penetration. Treatment shows strong efficacy with 78% of patients achieving PSA 90 response and 65% reaching PSA levels below 0.2. The safety profile appears favorable with mainly grade 1-2 fatigue and hypertension, though some patients experience gynecomastia. No patients discontinue treatment due to adverse events at 12 weeks. Future analyses will examine metabolic changes and quality-of-life measures.
Biographies:
Xin Gao, MD, Medical Oncologist, Assistant Professor of Medicine, Harvard Medical School, Massachusetts General Hospital, Boston, MA
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, MA
Biographies:
Xin Gao, MD, Medical Oncologist, Assistant Professor of Medicine, Harvard Medical School, Massachusetts General Hospital, Boston, MA
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, MA
Read the Full Video Transcript
Alicia Morgans: Hi! I'm so excited to be here today with Dr. Xin Gao, who is joining me from Massachusetts General Hospital in Boston at GU ASCO 2025, where we're talking about the ARAMON study. Such an interesting study of darolutamide as a single agent in patients with prostate cancer. Thank you for being here.
Xin Gao: Thanks so much for having me. It's an honor to be here.
Alicia Morgans: Wonderful. So tell me a little bit about this study. I think it's really innovative and certainly has my curiosity piqued.
Xin Gao: Sure. So ARAMON was a single-arm phase II clinical study involving darolutamide monotherapy. So that's without ADT in patients with biochemically recurrent prostate cancer. And the primary endpoint of this study was looking at serum testosterone levels at 12 weeks on therapy. And we looked at secondary endpoints, including PSA response measurements as well as safety.
Alicia Morgans: So tell me, what would you expect to find if you're giving a single-agent ARPI? I mean, we learned some of this from the EMBARK trial, but it is innovative in this setting.
Xin Gao: Yeah. So there were earlier studies involving enzalutamide monotherapy, apalutamide monotherapy roughly in this patient population. They were both smaller studies even compared to, obviously, EMBARK. And those studies show that serum testosterone levels increased by about 114% for enzalutamide monotherapy, 134% compared to baseline for apalutamide monotherapy.
So we know that anti-androgen therapy monotherapy will increase serum testosterone levels. Darolutamide is structurally pretty unique as compared to the other androgen receptor inhibitors. There's preclinical data suggesting that it crosses the blood-brain barrier to a much lower extent, as compared to other androgen receptor inhibitors.
And so the hypothesis is really that because of less central activity, there may be less reactive peripheral increases in serum testosterone levels. And potentially that may be associated with a more favorable toxicity profile.
Alicia Morgans: Interesting. So tell me, what did you find?
Xin Gao: So what we saw was that at 12 weeks on therapy on darolutamide monotherapy, serum testosterone levels increased by about 53.5% compared to baseline. And actually, based on preclinical data, we thought that that was around where we would see, and it was nice to see that, obviously. The testosterone levels increased to about 50% pretty early on by about four weeks on therapy, and maintained at that level through 12 weeks.
Alicia Morgans: Great. And were there any other endpoints that you investigated beyond the testosterone levels?
Xin Gao: Yes. So we looked at secondary endpoints of PSA response measurements. So PSA 90, PSA decreases to less than 0.2 at 12 weeks—a relatively early time point. And about 78% of patients saw a PSA 90, and about 65% of patients achieved a PSA of less than 0.2.
Now, the starting PSA values, I think the median was around 6. The max was upwards of, I think, 27 or 28. So there was a wide range. But we certainly saw PSA response activity there.
Alicia Morgans: That's great. Was there anything that you were able to report in this particular presentation around safety or adverse events?
Xin Gao: Yeah. So we were really interested in that—if testosterone levels don't increase as much as we might expect with other monotherapies, does that mean—is that associated with any meaningful changes in safety or toxicity? And I think we saw a relatively favorable safety profile with monotherapy.
We saw grade 1 to 2 fatigue and hypertension as the most common AEs. I think that's expected. But the rates were relatively low. This was a pretty small study, 24 patients total. And we saw five patients with grade 1 to 2 hypertension, four patients with grade 1 to 2 fatigue. And I think that compares pretty favorably with what we would expect with other therapies—systemic therapies—in this space.
We did see gynecomastia, breast tenderness, nipple tenderness or pain. And that's a common side effect that we see with ARI monotherapies. And that's related to the increases in serum testosterone levels and conversion to estrogens. And we did see that as well in our study. There was one case—one patient with a grade 3 gynecomastia. And patients did make use of tamoxifen and other therapies to try to manage that—a couple of patients, it wasn't a lot. None of the patients had received prophylactic breast irradiation to try to mitigate this beforehand.
We saw relatively low discontinuation rates of this monotherapy. So at 12 weeks, there were no patients who had discontinued therapy due to treatment-emergent adverse events. One patient did discontinue after 12 weeks due to gynecomastia.
Alicia Morgans: OK. So as you think about next steps, and obviously, you're not going to take a 24-patient trial where you're kind of investigating all of this safety and PSA and testosterone and jump right into clinic with it. But sometimes patients end up getting a single agent or pathway inhibitor as just part of their care because of other limitations. Do you take anything—or would you take anything that you learned in this trial so far as you move forward into clinic, even things like prophylactic breast irradiation or other strategies to try to make things more tolerable for patients?
Xin Gao: Yeah. I think it's about what trade-offs you want to make in terms of the safety or toxicity profile, right? Certainly, there are a number of, I would say, reasonable options in this space of biochemically recurrent prostate cancer. And it's about which side effects are acceptable or hopefully milder or more manageable for the patient.
Certainly with AR inhibitors, we see the gynecomastia, the breast tenderness being the biggest side effect, I would say, relative to, say, ADT. And we obviously have bigger data from EMBARK on enzalutamide monotherapy and, again, efficacy activity there with, again, some trade-offs in terms of the toxicity profile.
I think with darolutamide, we are seeing a very favorable profile. And I think that's not unexpected to a large extent based on what we knew before and placebo-controlled trials in combination with ADT. But it's nice to see that this has panned out, at least in this small study of monotherapy.
Alicia Morgans: Absolutely. So where do you go from here? What else would you like to investigate within this trial?
Xin Gao: Yeah. So we've collected additional endpoints. So patients receive treatment for upwards of 52 weeks on study. And if they were still benefiting, there's an option to continue even beyond that. But between 12 weeks and 52 weeks, we've collected additional measurements—metabolic changes, DEXA scans, a number of quality-of-life measures—and so we're interested in looking more deeply into that data that's starting to come to light.
Alicia Morgans: Wonderful. So what would your main message be—take-home for the listeners today as they consider this abstract?
Xin Gao: So I think darolutamide really is shown to be a pretty unique AR inhibitor in terms of the structure, the chemical structure, the effects on serum testosterone levels. I think we do see that it seems to be a bit different than some of the other AR inhibitors. And I think the safety profile with monotherapy appears to be pretty favorable, again, in this small study, that if there's interest, it certainly would make sense to try to look at it in a larger population of patients.
Alicia Morgans: Well, thank you so much for sharing your insights. Congratulations on your presentation at GU ASCO. I always appreciate talking to you.
Xin Gao: Thanks so much. Really appreciate it.
Alicia Morgans: Hi! I'm so excited to be here today with Dr. Xin Gao, who is joining me from Massachusetts General Hospital in Boston at GU ASCO 2025, where we're talking about the ARAMON study. Such an interesting study of darolutamide as a single agent in patients with prostate cancer. Thank you for being here.
Xin Gao: Thanks so much for having me. It's an honor to be here.
Alicia Morgans: Wonderful. So tell me a little bit about this study. I think it's really innovative and certainly has my curiosity piqued.
Xin Gao: Sure. So ARAMON was a single-arm phase II clinical study involving darolutamide monotherapy. So that's without ADT in patients with biochemically recurrent prostate cancer. And the primary endpoint of this study was looking at serum testosterone levels at 12 weeks on therapy. And we looked at secondary endpoints, including PSA response measurements as well as safety.
Alicia Morgans: So tell me, what would you expect to find if you're giving a single-agent ARPI? I mean, we learned some of this from the EMBARK trial, but it is innovative in this setting.
Xin Gao: Yeah. So there were earlier studies involving enzalutamide monotherapy, apalutamide monotherapy roughly in this patient population. They were both smaller studies even compared to, obviously, EMBARK. And those studies show that serum testosterone levels increased by about 114% for enzalutamide monotherapy, 134% compared to baseline for apalutamide monotherapy.
So we know that anti-androgen therapy monotherapy will increase serum testosterone levels. Darolutamide is structurally pretty unique as compared to the other androgen receptor inhibitors. There's preclinical data suggesting that it crosses the blood-brain barrier to a much lower extent, as compared to other androgen receptor inhibitors.
And so the hypothesis is really that because of less central activity, there may be less reactive peripheral increases in serum testosterone levels. And potentially that may be associated with a more favorable toxicity profile.
Alicia Morgans: Interesting. So tell me, what did you find?
Xin Gao: So what we saw was that at 12 weeks on therapy on darolutamide monotherapy, serum testosterone levels increased by about 53.5% compared to baseline. And actually, based on preclinical data, we thought that that was around where we would see, and it was nice to see that, obviously. The testosterone levels increased to about 50% pretty early on by about four weeks on therapy, and maintained at that level through 12 weeks.
Alicia Morgans: Great. And were there any other endpoints that you investigated beyond the testosterone levels?
Xin Gao: Yes. So we looked at secondary endpoints of PSA response measurements. So PSA 90, PSA decreases to less than 0.2 at 12 weeks—a relatively early time point. And about 78% of patients saw a PSA 90, and about 65% of patients achieved a PSA of less than 0.2.
Now, the starting PSA values, I think the median was around 6. The max was upwards of, I think, 27 or 28. So there was a wide range. But we certainly saw PSA response activity there.
Alicia Morgans: That's great. Was there anything that you were able to report in this particular presentation around safety or adverse events?
Xin Gao: Yeah. So we were really interested in that—if testosterone levels don't increase as much as we might expect with other monotherapies, does that mean—is that associated with any meaningful changes in safety or toxicity? And I think we saw a relatively favorable safety profile with monotherapy.
We saw grade 1 to 2 fatigue and hypertension as the most common AEs. I think that's expected. But the rates were relatively low. This was a pretty small study, 24 patients total. And we saw five patients with grade 1 to 2 hypertension, four patients with grade 1 to 2 fatigue. And I think that compares pretty favorably with what we would expect with other therapies—systemic therapies—in this space.
We did see gynecomastia, breast tenderness, nipple tenderness or pain. And that's a common side effect that we see with ARI monotherapies. And that's related to the increases in serum testosterone levels and conversion to estrogens. And we did see that as well in our study. There was one case—one patient with a grade 3 gynecomastia. And patients did make use of tamoxifen and other therapies to try to manage that—a couple of patients, it wasn't a lot. None of the patients had received prophylactic breast irradiation to try to mitigate this beforehand.
We saw relatively low discontinuation rates of this monotherapy. So at 12 weeks, there were no patients who had discontinued therapy due to treatment-emergent adverse events. One patient did discontinue after 12 weeks due to gynecomastia.
Alicia Morgans: OK. So as you think about next steps, and obviously, you're not going to take a 24-patient trial where you're kind of investigating all of this safety and PSA and testosterone and jump right into clinic with it. But sometimes patients end up getting a single agent or pathway inhibitor as just part of their care because of other limitations. Do you take anything—or would you take anything that you learned in this trial so far as you move forward into clinic, even things like prophylactic breast irradiation or other strategies to try to make things more tolerable for patients?
Xin Gao: Yeah. I think it's about what trade-offs you want to make in terms of the safety or toxicity profile, right? Certainly, there are a number of, I would say, reasonable options in this space of biochemically recurrent prostate cancer. And it's about which side effects are acceptable or hopefully milder or more manageable for the patient.
Certainly with AR inhibitors, we see the gynecomastia, the breast tenderness being the biggest side effect, I would say, relative to, say, ADT. And we obviously have bigger data from EMBARK on enzalutamide monotherapy and, again, efficacy activity there with, again, some trade-offs in terms of the toxicity profile.
I think with darolutamide, we are seeing a very favorable profile. And I think that's not unexpected to a large extent based on what we knew before and placebo-controlled trials in combination with ADT. But it's nice to see that this has panned out, at least in this small study of monotherapy.
Alicia Morgans: Absolutely. So where do you go from here? What else would you like to investigate within this trial?
Xin Gao: Yeah. So we've collected additional endpoints. So patients receive treatment for upwards of 52 weeks on study. And if they were still benefiting, there's an option to continue even beyond that. But between 12 weeks and 52 weeks, we've collected additional measurements—metabolic changes, DEXA scans, a number of quality-of-life measures—and so we're interested in looking more deeply into that data that's starting to come to light.
Alicia Morgans: Wonderful. So what would your main message be—take-home for the listeners today as they consider this abstract?
Xin Gao: So I think darolutamide really is shown to be a pretty unique AR inhibitor in terms of the structure, the chemical structure, the effects on serum testosterone levels. I think we do see that it seems to be a bit different than some of the other AR inhibitors. And I think the safety profile with monotherapy appears to be pretty favorable, again, in this small study, that if there's interest, it certainly would make sense to try to look at it in a larger population of patients.
Alicia Morgans: Well, thank you so much for sharing your insights. Congratulations on your presentation at GU ASCO. I always appreciate talking to you.
Xin Gao: Thanks so much. Really appreciate it.