Triple therapy and treatment sequencing in mHSPC: What ARASEC adds to the conversation

The novel hybrid design used in the phase 2 ARASEC trial (NCT05059236)¹—and the broader question of how urologists should navigate an mHSPC treatment landscape with multiple effective agents—were the focus of a conversation with Michael S. Cookson, MD, MMHC, FACS, who addressed cross-trial comparisons, tolerability distinctions, and the evolving role of triple therapy in treatment sequencing. Cookson was interviewed at the 2026 American Urological Association Annual Meeting in Washington, DC.

On the question of interpreting ARASEC's propensity score-matched external control design, Cookson acknowledged the tension between methodologic idealism and practical necessity.

"If you're a purist, you want randomized, level one evidence from phase 3 randomized studies," he said. "But if you understand that you really can't go back in time and get that type of control group, I think it makes perfect sense." He noted that the clinical results are consistent with what has been observed across other agents in this space—no surprises—which itself lends credibility to the findings.

Cookson urged caution, however, when interpreting ARASEC's striking hazard ratios—PFS of 0.29 and OS of 0.50—in the context of cross-trial comparisons with enzalutamide (Xtandi) or apalutamide (Erleada).

"When you're talking about comparing different trials, that's tricky, and you're really not supposed to try to make apples-to-apples comparisons because there are differences in follow-up and study design," he said. His interpretation: The data validate that darolutamide (Nubeqa) works as well as other agents in this setting.

"All of those agents have shown overall survival benefit. This is affirming in that regard." Where meaningful differentiation does exist, he argued, is in tolerability and adverse event profiles—and even those must be interpreted with the caveat that each trial was designed differently.

On tolerability, Cookson identified darolutamide's limited CNS penetration and more favorable drug-drug interaction profile as potentially meaningful advantages for the mHSPC population, which tends to be older and polypharmacy-burdened.

"A lot of our patients are on certain blood thinners that may interact with the medication we're placing them on," he said. The absence of significant blood-brain barrier penetration may also reduce the risk of cognitive adverse events—a consideration in older patients for whom cognitive preservation is a quality-of-life priority.

Regarding treatment selection more broadly, Cookson expanded the conversation to include triplet therapy—a combination of an androgen receptor pathway inhibitor, docetaxel, and ADT—which he said must be part of any complete discussion of mHSPC management.

"If you have high-volume metastatic disease, particularly if it's de novo, those patients, if they're chemo-fit, could be considered for triplet therapy," he said, referencing the ARASENS trial (NCT02799602) in which darolutamide was combined with chemotherapy and ADT. For lower-volume or oligometastatic disease — increasingly detected on PSMA-PET—doublet therapy may be sufficient. Ongoing studies are exploring whether a response-adapted approach, escalating to chemotherapy only in patients with inadequate doublet response at 6 months, can spare some patients the toxicity of upfront triple therapy.

On the broader implications of ARASEC's design as a potential model for future trials, Cookson deferred on the statistical details while endorsing the conceptual value.

"The idea is there—you might be able to use an active agent and compare it to a very well-matched control," he said. "It's probably never going to be as convincing as a truly randomized study, but it could be a pathway to enhanced drug discovery in an area where an already established standard of care limits your ability to have a control arm."

REFERENCE

1. McKay R, et al. ARASEC: A novel pragmatic trial design comparing darolutamide plus ADT versus ADT in US patients with metastatic hormone-sensitive prostate cancer using propensity score matching with an external phase 3 trial control arm. J Urol. 2025;213(5S). doi:10.1097/01.JU.0001109788.ARASEC