ARAMIS Reinforces Findings from ARASENS and Other Studies of Darolutamide in nmCRPC

Neal D. Shore, MD, FACS

Darolutamide (Nubeqa) led to a safety profile that was maintained in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC), according to long-term data from the phase 3 ARAMIS trial (NCT02200614).

Findings revealed that treatment with darolutamide led to approximately 30% of patients with nmCRPC remaining on treatment for at least 4 years.

In 2019, the FDA approved darolutamide for the treatment of patients with nmCRPC based on results of the double-blind, randomized, multicenter phase 3 ARAMIS trial that has an open-label, rollover study as well (NCT04464226).

Previously, findings from ARAMIS showed that treatment with darolutamide led to significantly improved metastasis-free survival rates and it reduced the risk of death compared with placebo in this patient population.The final analysis of the study showed that darolutamide continued to significantly reduce the risk of death by 31% vs placebo.

A total of 954 patients were given darolutamide on randomization, and 294 (31%) entered the rollover study. Looking at safety, the incidence of treatment-related adverse events increased slightly over time, but this was expected with longer observation time.

Overall, these findings support long-term use of darolutamide in patients with nmCRPC.

In an interview with Targeted Oncology^TM, Neal D. Shore, MD, FACS, the director of the Carolina Urologic Research Center, Atlantic Urology Clinics in Myrtle Beach, South Carolina, gave an overview of previous and updated findings from the ARAMIS trial for patients with nmCRPC.

Targeted Oncology: Can you provide a recap of the primary analysis result from ARAMIS?

Shore: ARAMIS was a global, phase 3, prospective, double-blind, randomized, control trial, where we were investigating the impact of darolutamide vs a control placebo for patients with an nmCRPC. By conventional imaging, CT scan, bone scans were no finding of metastatic disease and they had to have had a rising PSA specifically with a PSA doubling time of less than 10 months.

The primary end point of the ARAMIS trial was metastasis-free survival, which we achieved in this patient population. For men, that was highly statistically significant. Additionally, a key secondary end point in a hierarchical fashion was overall survival. That also met statistical significance. The findings of both the primary end point of both, the metastasis-free survival, as well as a secondary end point of overall survival, led to 2 separate New England Journal publications.

What data came from the sub-analysis of the study?

In the sub-analysis of the study, we [compared] patients in the treatment arm, in other words, those who received continued ADT with darolutamide 300 mg [twice daily] vs those in the control arm receiving continued ADT and a placebo. We looked at secondary end points of overall survival, treatment-related pain, time to secondary next antineoplastic therapy, as well as overall quality-of-life measures. Fortunately, in all of our secondary end points, we showed the benefit of treatment with darolutamide vs continuing ADT with a placebo control.

For the long-term safety analysis, what were the study methods used?

What was nice and rewarding for us regarding the long-term safety in a particular abstract that was accepted at GU ASCO 2023 is that we looked at patients who maintained therapy and who were in the double blind, and then we're in the open-label extension, as well as patients in the crossover. Nearly 30% of our patients ended up staying on darolutamide in this nmCRPC population for over 4 years, which is quite a significant number of patients. Not only did it delay progression of disease, radiographic progression, or what we often now have in these particular studies of the composite end point of metastasis-free survival, but the tolerability and the safety was prolonged with treatment. We demonstrated that there were no new safety concerns, putting it as simplistically as possible. I think that this speaks to the tolerability of this very active androgen receptor blocker.

Can you explain the updated results?

The main findings were that the clinical benefit and the favorable safety profile of darolutamide for patients with nmCRPC has now been maintained for several years. Treatment-emergent adverse events that we have a list of through careful trial definitions were essentially consistent in terms of any grade, or grade 3, or 4. Even the issues regarding discontinuation that were treatment-related. In the data that we presented, it's slightly increased over time, as what would be expected, but the differences in the increase are small. We also looked at exposure. One of the ways that we looked at that was with an exposure adjustment analysis, where we looked at fatigue, fall and fracture, rash, mental impairment, hypertension, the types of [adverse events] that are often seen throughout the class of androgen receptor signaling inhibitor drugs.

What we found was that this incidence was not only low, essentially single digits with the exception of 1 slightly above that for fatigue at 14%. This was virtually single digit in fall, fracture, rash, and mental impairment disorder, not only for the original trial presentation in our first publication, but now in this rollover for the 30% of patients staying on drug out to north of 4 years. There was a minimal increase in those percentages of [adverse event] experiences. This should be reassuring to patients who tend to be elderly who have nmCRPC, who are elderly as the average age is over 70 in these studies, but also reassuring to physicians as we're starting patients on a therapy that, other than having the [adverse events] of T suppression, they typically are not having any others because they don't have any demonstrable tumor burden on conventional imaging. Therefore, adding another drug, like darolutamide, overall has demonstrated, in its long-term and in this rollover, its safety profile.

What do these findings mean for darolutamide moving forward?

For darolutamide, it further reinforces other studies that we've done and have further long-term follow-up for. For example, the ARASENS trial (NCT02799602), which was a study conducted for men with both low and high volume mHSPC. After several years of follow-up for those patients, a different patient population, and also these patients that were combined with a 4-month course of docetaxel, what we see in the long-term rollover study of ARAMIS and what we also saw in ARASENS is that the tolerability and the safety profile is highly consistent for darolutamide. One of the reasons why I think many feel that it’s well-tolerated, especially on the neurocognitive spectrum which includes fatigue, is that it’s been shown in preclinical models not to penetrate the blood brain barrier. I think this is important for those on the spectrum of neurocognitive [adverse events].

How would you advise community oncologists on managing toxicities associated with this agent?

Like with any agent, if you come across a toxicity that you’re concerned about, one can hold the drug and see how that affects the specific [adverse events]. There’s an opportunity because darolutamide is 2 pills, so you can reduce the dose, or you can do a hold dose reduction. There is flexibility there for specific adverse events such as fatigue. I'm a big proponent of talking to patients with multiple different stages and different therapies. This could include darolutamide, the importance of a low carbohydrate, plant-based diet to avoid swings in glucose and insulin release. There is clearly a large body of evidence supporting that. Nutritional guidance and regular exercise, a combination of both, resistance exercise for muscle growth, muscle build, and a cardiac exercise. I think those 2 strategies, as simplistic as they sound, are extremely important for all our patients with cancer, particularly those who are on oncolytic therapies.

Regarding prostate cancer research, what are you most excited about seeing this year?

So far this year, we saw some additional data from PROpel [NCT03732820], the pre-specified, final analysis of the cut-off for the third analysis. Then also the data that from TALAPRO-2 (NCT03395197). Both of these trials looked at combinations of a PARP inhibitor and an androgen receptor blocker. PROpel was an all-comer population with first-line nmCRPC [treated with] olaparib [Lynparza] and abiraterone [Zytiga] vs the control of abiraterone. TALAPRO-2 had a similar patient population, but combined enzalutamide [Xtandi] with talazoparib [Talzenna] vs the control of enzalutamide and a placebo control. What was bold of both of these studies was that they looked at an all-comer population, but at the same time, interrogated for [homologous recombination repair] mutations. There were some nuanced differences of how that was done in both studies, but at the end of the day, both met their primary end point in an all-comer population.

There is a lot of ongoing conversation and education that is permeating to the urologic oncology, medical oncology, and the radiation oncology communities to understand why these 2 studies, being both positive, are important for having an understanding of the data in both the mutation-positive, mutation-negative, in the all comers population, the safety, [adverse event] profiles, and how it can best offer their understanding of these trials as another new opportunity to advance patient care and decision making. Both studies will ultimately be in front of the FDA in 2023, and we're certainly optimistic that they can ultimately get regulatory approval.

Can you briefly discuss any other projects you're working on right now?

I'm honored and privileged to be involved in numerous phase 1 and phase 2 studies and some important phase 3 trials looking at ways to lower resistance to the androgen receptor, and of course, looking at new targeted therapies with novel mechanisms of action outside of the already 7 novel mechanisms of action that we have approved in the United States today. I am excited, both for the new mechanism of action therapies, but also for combinations and trials to decrease resistance to the androgen receptor.