Darolutamide Doublet Is Redefining Treatment Decision-Making for mCSPC

Treatment intensification has reshaped the management of metastatic castration-sensitive prostate cancer (mCSPC), with ongoing debate regarding the optimal use of doublet vs triplet regimens, according to Matthew R. Smith, MD, PhD.

Darolutamide (Nubeqa), which was initially investigated in combination with androgen deprivation therapy (ADT) and docetaxel in the phase 3 ARASENS trial (NCT02799602), demonstrated superior time to mCRPC and overall survival (OS) in the triplet arm vs placebo arm.1 Given these results, questions remained about whether ADT plus darolutamide alone could provide meaningful benefit, Smith noted.

The subsequent phase 3 ARANOTE trial (NCT04736199) addressed this gap. Findings from ARANOTE, which supported the July 2025 FDA approval of darolutamide, showed that darolutamide plus comcomittant ADT resulted in a 46% reduction in the risk of radiological progression or death vs placebo and ADT. The median radiographic progression-free survival (rPFS) was not reached (NR; 95% CI, NR-NR) vs 25.0 months (95% CI, 19.0-NR), respectively (HR, 0.54; 95% CI, 0.41-0.71; P < .0001).2,3

In an interview with OncLive®, Smith discussed how the ARANOTE trial clarified the role of darolutamide as doublet therapy, the broader clinical implications of this approval, and how these data influence treatment decision-making in practice.

Smith is director of the Genitourinary Oncology Program at Massachusetts General Hospital Cancer Center and an associate professor of medicine at Harvard Medical School.

OncLive: How did the ARANOTE trial clarify the role of darolutamide plus ADT in mCSPC

Smith: The prostate cancer space is very active, and there has been a lot of progress in the field. One of the biggest changes in the management of metastatic prostate cancer has been treatment intensification as initial systemic therapy, specifically in [mCSPC]. There are a lot of [important] questions and ongoing controversies about doublet vs triplet therapy.

Darolutamide was first developed in mCSPC as part of triplet therapy, based on the treatment landscape at the time. That left a gap [in understanding] whether doublet therapy [comprising] ADT plus darolutamide would also be effective with strong prospective data. That is really where the ARANOTE trial came in. My presentation spent a good amount of time describing the design of the ARANOTE study, the rationale behind it, and the strong evidence that supported the expanded label of darolutamide as doublet therapy for mCSPC.

Considering the ongoing debate between doublet and triplet therapy in mCSPC, in which patient populations would you consider using each option?

Although we have a strong body of high-level evidence supporting treatment intensification, the actual application of that evidence in routine practice has lagged. Many patients in the United States [US] still receive ADT alone as initial systemic therapy for metastatic disease. That may be appropriate for a small minority of patients with very mild disease, or for older, frail patients who may not be good candidates for intensification.

The most important thing we can do as a community is to practice evidence-based medicine and at least provide doublet therapy [with] ADT plus an androgen receptor pathway inhibitor (ARPI) to the vast majority of patients with mCSPC.

The secondary question is, who should also receive chemotherapy with [docetaxel] in addition to the ADT/ARPI doublet? That is a question we probably will never completely answer in a prospective randomized controlled trial. Therefore, we are left interpreting data from the ADT/[docetaxel] doublets, as well as from the triplet studies, such as [ADT plus darolutamide with or without docetaxel, ARASENS, and the comparable [phase 3] study with ADT plus abiraterone (Zytiga) with or without docetaxel, PEACE-1 [NCT01957436)].

These triplet studies did not specifically address the role of [docetaxel]; they addressed the role of the ARPI. We now know that ADT plus an ARPI is the standard of care, and the question of whether to add [docetaxel] remains secondary and based on our best interpretation of imperfect data. [Accordingly,] we are left with a gap in evidence.

In my practice, and for many colleagues across the country, we reserve triplet therapy primarily for the youngest, healthiest patients, who are the least likely to be harmed by the addition of [docetaxel] and most likely to benefit because of the severity of their disease, such as those with de novo, high-burden metastatic disease. There may also be a role for other predictors of poor outcomes, including tumor genetic testing, loss of tumor suppressor genes, or high Decipher scores. These are being investigated but have not yet been validated as predictive biomarkers.

What is the clinical significance of the FDA approval of darolutamide with ADT, and how might it influence treatment decision-making in your practice?

We had adopted ADT plus [darolutamide] long before the formal label expansion. Most key opinion leaders in the field would share [my view] that is that [ARPIs] have similar efficacy across the entire spectrum of prostate cancer.

There are different studies supporting that, done at different times in somewhat different patient populations, so we can compare across trials better than we can in many other cancer settings. The main conclusion is that the ARPIs have similar efficacy to each other across the spectrum of prostate cancer.

They do have differences in tolerability—the adverse effect profile, safety, drug–drug interactions, all of that. I view them as interchangeable for efficacy, but there may be reasons for specific patient selection based on safety.

[Therefore], it’s important that [darolutamide] has this formal label, so we can use ADT plus [darolutamide] for appropriate patients. It is my preferred regimen, because it has similar efficacy but better safety and tolerability compared with the other agents, although I’d be the first to acknowledge that those other agents are also quite good.

If you look at any study in isolation, including [the ARANOTE trial (NCT04736199)], you can point out its limitations. ARANOTE was done in a more contemporary setting, it was performed outside of the US, and it doesn’t have mature overall survival data.

If I also wanted to pick out an individual study and [ask] which is the best for efficacy, I could argue that darolutamide has better data supporting, say, triplet therapy—which is the highest bar to cross than any other drug. The phase 3 ARAMIS trial [NCT02200614] also has among the best data [for darolutamide] in nonmetastatic CRPC for both overall survival and safety.

If you have your favorite ARPI, you can pick and choose different studies to support your argument, but at the end of the day, they’re all similarly effective, and darolutamide is best in class for safety.

References

1. Carles J, Tombal B, Hussain M, et al. Age-related efficacy and safety of darolutamide plus androgen-deprivation therapy (ADT) and docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC): A subgroup analysis of ARASENS. J Clin Oncol. 2025; 45(5): 143.doi:10.1200/JCO.2025.43.5_suppl.143
2. Saad F, Vjaters E, Shore N, et al. Darolutamide in combination with androgen-deprivation therapy in patients with metastatic hormone-sensitive prostate cancer from the phase III ARANOTE trial. J Clin Oncol. 2024;42(36):4271-4281. doi:10.1200/JCO-24-01798
3. FDA approves darolutamide for metastatic castration-sensitive prostate cancer. FDA. June 3, 2025. Accessed August 19, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-darolutamide-metastatic-castration-sensitive-prostate-cancer