ARANOTE Data Highlight Darolutamide Plus ADT as a Potential Chemo-Free Option in mHSPC

Fred Saad, MD, FRCS

The efficacy and safety displayed by the combination of darolutamide (Nubeqa) and androgen deprivation therapy (ADT) without the addition of docetaxel could allow for more personalized treatment decisions for patients with metastatic hormone-sensitive prostate cancer (mHSPC), according to Fred Saad, MD, FRCS.

Findings from the phase 3 ARANOTE trial (NCT04736199) presented at the 2024 ESMO Congress showed that patients treated with darolutamide in combination with ADT (n = 446) experienced a median radiographic progression-free survival (rPFS) that was not reached (NR; 95% CI, NR-NR) compared with 25.0 months (95% CI, 19.0-NR) for those given placebo plus ADT (n = 223; HR, 0.54; 95% CI, 0,41-0.71; P < .0001).

Saad explained that the study’s secondary end points also favored the darolutamide combination, including rates of prostate-specific antigen (PSA) below 0.2 ng/mL (62.6% vs 18.5%).

“There was more than a 3-fold increase in the number of patients achieving that ‘holy grail’ of [a PSA level of] less than 0.2 ng/mL,” Saad said in an interview with OncLive^®. “There were also significant delays in PSA progression, which is important in deciding next lines of therapy.”

In the interview, Saad highlighted the rationale for investigating darolutamide plus ADT without docetaxel in patients with mHSPC; expanded on the key efficacy and safety data from ARANOTE; and detailed the potential implications of the findings from the trial.

Saad is a genitourinary oncologist and the Raymond Garneau Chair in Prostate Cancer at the University of Montreal Hospital Center (CHUM) Research Center (CRCHUM), the head of Urology at CHUM, and the director of prostate cancer research at the Montreal Cancer Institute/CRCHUM.

OncLive: What was the rationale for the ARANOTE trial?

Saad: The rationale for ARANOTE was to ensure that darolutamide without chemotherapy would benefit patients with mHSPC. We already had the phase 3 [ARASENS trial (NCT02799602)] that showed darolutamide combined with docetaxel [and ADT] clearly improved OS over ADT plus docetaxel alone.

[Data from ARASENS] led to approval and use for [darolutamide plus docetaxel in patients with mHSPC]. However, there are patients who might not need or be able to tolerate docetaxel. Therefore, [building evidence] to be able to offer darolutamide without docetaxel was an important rationale for establishing the ARANOTE study.

What was the design of this trial and what patient population was enrolled?

The patients we enrolled all had mHSPC that could be de novo or metachronous, meaning [patients who received] localized therapy and then [experienced] recurrence that was found to be metastatic. We included 669 patients who were randomly assigned 2:1 between darolutamide plus ADT vs ADT plus placebo with a primary end point of rPFS or death. Secondary end points included OS, but there were multiple end points that were important to patients and for us to realize whether we were benefiting patients with this treatment.

What were some of the key efficacy findings presented at the 2024 ESMO Congress?

The study met its primary endpoint. We reduced [the risk of] rPFS or death by 46% [HR, 0.54; 95% CI, 0.41-0.71; P < 0.0001]. All subgroups in the study, including those with de novo disease and high-volume disease, benefited from the addition of darolutamide to ADT compared with ADT alone.

Additionally, all secondary end points favored the combination of darolutamide plus ADT.

OS [data] were immature, but we did see a 19% reduction in the risk of death. The other end points were all in favor of darolutamide, including delaying the time to metastatic castration-resistant disease, delaying the time to pain progression for patients, and we had much higher rates of [patients achieving] undetectable prostate-specific antigen below 0.2 ng/mL.

What is the safety profile of this combination?

The safety profile was an important component because there are still some unmet needs in terms of trying to minimize the burden of additional therapy over ADT in men with metastatic disease. We already had two [phase 3] studies—ARASENS and ARAMIS [NCT02200614]—using darolutamide that showed a promising safety profile.

[Data from ARANOTE] add to the safety profile. Darolutamide combined with ADT showed minimal, if any, difference [in safety] compared with patients given placebo, which was reassuring.

We saw fewer patients discontinue darolutamide compared with those who discontinued placebo [due to] adverse effects [AEs]. We saw less fatigue in patients on darolutamide vs patients on placebo. It is encouraging that it was difficult to see the difference between darolutamide and placebo in terms of safety profiles.

Are there any next steps that are planned to keep investigating darolutamide in prostate cancer?

There are a lot of initiatives that are going on. Since the safety profile is good and the efficacy is excellent, [we are] looking at [evaluating the agent in] even earlier settings of prostate cancer prior to mHSPC. Those are things that are in the works, and trials are ongoing. It's an interesting drug to look at in combinations since we're able to safely administer this with many drugs with little fear of worsening the AE profiles of combinations, and the drug-to-drug interactions are quite encouraging,

What are the potential clinical implications of data from ARANOTE?

We hope that this will become another standard of care for patients using what we consider now the best baseline standard of care for mHSPC, which means ADT plus an androgen receptor pathway inhibitor [APRI]. We already have effective ARPIs available around the world, and this will add to those therapeutic options to try to tailor treatment for patients based on their needs and particular [disease] profiles. Since we already have darolutamide plus ADT and docetaxel available, this could allow us to consider ADT plus darolutamide with or without docetaxel, based on patient needs and preferences.

Reference

Saad F, Vjaters E, Shore ND, et al. Efficacy and safety of darolutamide plus androgen-deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) from the phase III ARANOTE trial. Ann Oncol. 2024;35(suppl 2):S1257-S1258. doi:10.1016/j.annonc.2024.08.2311