Darolutamide/ADT Continues to Demonstrate Favorable Tolerability in Nonmetastatic CRPC

Neal D. Shore, MD, FACS, highlights the role of darolutamide plus androgen deprivation therapy and how it continues to demonstrate a highly favorable tolerability and safety profile in patients with nonmetastatic castration-resistant prostate cancer.

Darolutamide (Nubeqa) plus androgen deprivation therapy (ADT) continued to demonstrate a highly favorable tolerability and safety profile in patients with nonmetastatic castration-resistant prostate cancer (CRPC), according to Neal D. Shore, MD, FACS, who added that real-world data comparing androgen receptor (AR) inhibitors will be the focus of future efforts.

In the double-blind, randomized, multicenter, global, phase 3 trial, 1509 patients with nonmetastatic CRPC and a prostate-specific antigen (PSA) doubling time of 10 months or less were randomized 2:1 to receive 600 mg of darolutamide twice daily (n = 955) or placebo (n = 554) while continuing ADT. The primary end point of the study was metastasis-free survival (MFS).

Updated results presented during the 2020 ESMO Virtual Congress showed that the recommended dose of darolutamide was well tolerated, and the majority of patients were able to receive their full planned dose.

The median time of treatment was 14.8 months with darolutamide and 11.0 months with placebo. The number of dose modifications proved to be comparable between the 2 treatment arms, at 15.2% in the darolutamide arm versus 9.7% in the placebo arm. Notably, dose modifications were mainly due to adverse effects (AEs). Almost all patients who experienced dose modifications in either arm were able to be re-escalated to the full planned dose. Additionally, the incidence of treatment discontinuation because of AEs also were similar between the investigative and control arms, at 8.9% versus 8.7%, respectively.

Furthermore, the majority, or 83.6%, of patients who received darolutamide experienced a PSA response versus 7.6% of those who were given placebo. The median PSA decrease from baseline was 91.7% with darolutamide versus 31.9% with placebo.

“We demonstrated that by combining darolutamide with ADT in patients with nonmetastatic CRPC, we could delay metastasis by nearly 2 years. Knowing this, patients and physicians alike feel much better,” said Shore. “Notably, metastasis correlates with pain and the need for additional anticancer therapies, such as chemotherapy.”

Regarding safety, common treatment-emergent AEs included cardiac failure, cardiac arrest, hypertension, cerebral infarction, cerebrovascular accident, ischemic stroke, pulmonary embolism, pneumonia, and acute respiratory failure, among others.

In an interview with OncLive, Shore, the medical director of the Carolina Urologic Research Center, discussed the updated findings from the phase 3 ARAMIS trial with darolutamide and ADT, the impact of these data, and other key efforts being made in nonmetastatic CRPC.

OncLive: Could you speak to the unmet needs faced in nonmetastatic CRPC prior to the ARAMIS trial?

Shore: Even when PSA levels are rising and testosterone levels are under the castration range, conventional imaging with CT and bone scans may show up negative. We know that microscopic disease is causing the PSA level to rise.

Results from earlier studies have shown that the faster that PSA rises over time correlates with the development of tumor burden progression on imaging. Usually, it'll be the development of bone metastasis; it can also be soft tissue lymph nodes, visceral metastases, or combinations of those.

Until recently, we haven't had much level 1 evidence to [be able to] offer patients a therapy that can delay the progression of positive findings on imaging. In addition to that, the concern about progression is that it leads to tumor burden, symptoms, pain, and [the need for] additional anti-neoplastic therapies. Ultimately, it starts the clock ticking on a decrease in survival.

If we look back to the initial American Urological Association CRPC guidelines, we had no level 1 evidence to offer patients a therapy that would decrease their risk of developing radiographic progression or death.

What was the goal of ARAMIS? What were the previous data that have read out?

The ARAMIS trial was designed with a primary end point of MFS, which went through a lot of thoughtful consideration and discussion with regulatory agencies. We previously presented the initial primary end points findings, which were positive, and published them in the New England Journal of Medicine. These data showed that the primary end point of MFS was met.

At the 2020 ASCO Virtual Scientific Program, and again at the 2020 ESMO Virtual Congress, we presented the secondary end point benefit of overall survival (OS). Interestingly, in our study, OS was at the top of the list for secondary end points. Due to the hierarchical order, if OS was not met, all the additional secondary end points could not be reviewed.

Our study is the largest nonmetastatic CRPC trial to be performed to date in terms of the population. Over 1500 men were randomized 2:1 to receive darolutamide plus persistent ADT or persistent ADT plus placebo. We met our hazard ratio on the initial analysis, which was 0.41, and we published that in the New England Journal of Medicine. However, at that time, the number of deaths was very low. It wasn’t until little over 1.5 years later, when we published a second article in the New England Journal of Medicine, that we were able to clearly demonstrate the OS benefit [of the approach], with a hazard ratio of 0.69.

What additional insights were revealed during the 2020 ESMO Virtual Congress?

During the 2020 ESMO Virtual Congress, we reviewed the final analysis; this is probably one of the most compelling aspects of the trial in comparison with the other 2 successful nonmetastatic CRPC trials that have received level 1 evidence for MFS and OS. The big difference with darolutamide versus the other AR signaling inhibitor drugs is that its molecular structure is markedly different; it’s a much larger molecule and has a polarity as part of its organic chemistry. The significance is that it's less lipophilic and we theorize that it’s much less likely to penetrate the blood–brain barrier. We demonstrated that in animal models, not human models, since that would have been much more challenging to do. However, when you can avoid the blood brain–barrier penetration, the [hypothesis] is that you avoid the stimulation of GABA receptors, which can result in seizures, or lower the seizure threshold potential.

This explains why, in all of the early-phase darolutamide trials, including ARAMIS, patients who have a history of seizures, are on seizure-lowering medications, or who have a history of transient ischemic attacks or cerebrovascular accidents, were all allowed to enroll. In fact, we had 12 patients on ARAMIS who had a documented history of seizures. This was not the case in other nonmetastatic CRPC studies. We evaluated other important reasons for potentially discontinuing therapy on either of the arms, and the number of patients who discontinued treatment because of [treatment-emergent] AEs ended up being the same.

When looking at the AEs, minimal differences were observed between the darolutamide and placebo arms with regard to cardiac events, which is extremely impressive from a cardiology standpoint. Additionally, we examined neurological events, such as cognitive impairment, and did not find many differences [between the 2 arms], other than fatigue.

The long-term final analysis demonstrated very good tolerability [with darolutamide/ADT]. I believe this is somewhat unique to the medication, and I would like my colleagues to be familiar with this. I've had the good fortune to be involved in both the early phase and phase 3 study. Since its approval and accessibility on a global scale, I look forward to my colleagues obtaining real-world experience with this [approach]. The therapy consists of 2 pills that are taken twice daily with food.

Also, in addition to the obvious delay in radiographic progression and death, which was the MFS composite end point, over 80% of patients experienced a greater than 50% decline in their PSA levels at baseline; that’s certainly something that patients and family members would like to hear. I explain to them that not only will their PSA levels markedly [drop] with this drug, but [on average, it offers] 2 years of delayed imaging positivity; this translates to survival prolongation. Our final analysis showed very low rates of dose reduction and treatment discontinuation [with darolutamide/ADT]; they were similar to what was seen in the placebo arm.

Are any efforts comparing darolutamide with other AR inhibitors?

It's always exciting when we get a new drug to market that has some distinct advantages, especially with regard to its safety profile and tolerability. There is clearly efficacy benefit [with this approach], as well. I believe it’s important to conduct prospective direct comparator trials with other effective AR signaling inhibitor therapies. Those trials are ongoing in the mCRPC population, as opposed to the nonmetastatic CRPC population.

We have other trials comparing darolutamide with other AR inhibitors. We also need to perform neurocognitive and neuro-oncologic studies to better understand the implications of these therapies. Much like cardio-oncology has been gaining a tremendous amount of research, understanding, and publications over the years, I believe the field of neuro-oncology is truly burgeoning at this time.

Ultimately, this work will help us be better diagnosticians and managers, and help us to select therapeutics that are more favorable in terms of neuro-oncologic effects, particularly with regard to cognition and fatigue.

Are any other ongoing studies examining darolutamide that you wanted to highlight?

Regarding darolutamide, a large phase 3 trial evaluated testosterone suppression plus docetaxel with or without darolutamide in patients with metastatic hormone-sensitive prostate cancer (mHSPC), which is the ARASENS trial. Accrual has completed for this trial and that read out is pending. I believe other darolutamide/ADT trials will be done in the mHSPC space, without a taxane component.

Also, as with many of the AR signaling inhibitor drugs, we must determine whether these agents can be combined with PARP inhibitors or other immunologic agents such as checkpoint inhibitors, CTLA-4 antibodies, or radiopharmaceuticals like radium-223 dichloride (Xofigo).

A. Oliver Sartor, MD, of Tulane University, and I were co-principal investigators of a large phase 3 study where patients with mCRPC were randomized to receive either enzalutamide (Xtandi) or darolutamide. After a 12-week run-in, patients were randomized to either radium-223 or a placebo infusion.

The rationale of this study was to evaluate darolutamide in the mCRPC space, to assess other neuro-oncologic end points in comparison with enzalutamide, and to determine whether sequencing both enzalutamide and darolutamide and then bringing in radium-223 is better tolerated than starting that drug concomitantly. We wanted to determine whether [this approach] had a better impact on the bone micro-compartment. 

The PEACE III trial is combining radium-223 with enzalutamide. However, investigators are doing it in a concurrent, concomitant way, as opposed to a layered manner. I'm excited about darolutamide moving earlier on in the treatment journey for patients with prostate cancer.

Could you speak to the clinical significance of ARAMIS?

This was a very important study because it was globally conducted. About 75% to 80% of the patients came from Europe and Asia, and about 25% to 30% came from North America and Latin America. We can't conduct these studies without global cooperation, dedicated investigator sites, and, most importantly, the patients and their families who are willing to participate. Clinical trials are, and continue to be, the most important aspect of how we make advances in healthcare. I think it is so important that we keep getting that message out there.


Fizazi K, Shore N, Smith MR, et al. Tolerability and treatment response to darolutamide (DARO) in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) in the phase III ARAMIS trial. Presented at 2020 ESMO Congress; September 17, 2020; Virtual. Abstract 633P.