ARANOTE: Darolutamide improves HRQoL in mHSPC

In the phase 3 ARANOTE trial (NCT04736199), darolutamide (Nubeqa) plus androgen deprivation therapy (ADT) significantly delayed deterioration of health-related quality of life (HRQoL) compared with placebo in patients with metastatic hormone-sensitive prostate cancer (mHSPC), with notable improvements in pain and several HRQoL subscales.¹

Alicia Morgans, MD, MPH

“Darolutamide confers a positive impact on health-related quality of life, as assessed within this study. In ARANOTE, darolutamide demonstrates clinically meaningful delays in pain progression and in deterioration of important patient-related health-related quality of life outcomes vs placebo in patients with metastatic hormone-sensitive prostate cancer,” said presenting author Alicia Morgans, MD, MPH, a genitourinary medical oncologist and the director of the Survivorship Program at Dana-Farber Cancer Institute in Boston, Massachusetts, at the 2025 American Society of Clinical Oncology Annual Meeting in Chicago, Illinois.

At the beginning of her presentation, Morgans emphasized factors that are considered important to patients.

“Most people come to clinic because they wish to live longer, and I think we all recognize that, but they also have other concerns and considerations that they want us to be aware of as well. They want to control that PSA [prostate-specific antigen] level that stresses them out between each visit, and certainly as they wait for the result, they want to avoid treatment-related adverse events at all costs, if that is possible. They want to minimize pain and they want to minimize other symptoms that may impair them from doing the things that they wish. They want to maintain independence and their ability to support their families as they have for their lives before this diagnosis, and they certainly want to maintain well-being and quality of life as they engage in the things that truly make them happy,” Morgans said.

As Morgans recounted, data from the phase 3 ARANOTE trial indicated that treatment of mHSPC with darolutamide plus ADT significantly improved radiological progression-free survival (rPFS), with a reduced risk of radiological progression or death of 46% compared with placebo (HR 0.54; 95% CI: 0.41-0.71, P < .0001.²

Median patient age in ARANOTE was 70 years (range, 43-93 years) in the darolutamide arm and 70 years (range, 45-91 years) in the placebo arm. ECOG Performance Status was 0 in 52.7% of patients in the darolutamide arm vs 43.9% in the placebo arm, and 1-2 in 47.3% of the darolutamide arm and 56.1% in the placebo arm. Morgans highlighted the international nature of the cohort, with 31.6% of patients in the darolutamide arm and 28.3% of patients in the placebo arm being from Asia; 26.7% and 32.3% respectively, from Latin America; and 41.7% and 39.5%, respectively, from Europe/the rest of the world. Median serum PSA level 21 ng/mL (range, 0.02 ng/mL-15,915 ng/mL) in the darolutamide arm and 21 ng/mL (range, 0.02 ng/mL-8533 ng/mL) in the placebo arm. Disease volume by CHAARTED criteria was considered high in 70.6% of the darolutamide arm vs 70.4% of the placebo arm.

The HR for rPFS in ARANOTE was 0.54 (95% CI: 0.41-0.71, P < .0001). Median rPFS was not estimable (NA) in the darolutamide arm (95% CI: NE-NE) vs 25.0 months in the placebo arm (95% CI: 19.0-NE). Treatment-emergent adverse events (TEAEs) of any grade were seen in 91.1% of the darolutamide arm and 90.0% of the placebo arm. Grade 3-4 TEAEs were observed in 30.8% of the darolutamide arm vs 30.3% of the placebo arm. Grade 5 TEAEs were observed in 4.7% of the darolutamide arm vs 5.4% of the placebo arm. Serious TEAEs were seen in 23.6% of patients in the darolutamide arm vs 23.5% of the placebo arm, and TEAEs leading to permanent discontinuation of the study drug were observed in 6.1% of patients in the darolutamide arm vs 9.0% of patients in the placebo arm.

For the pain and HRQoL analyses of ARANOTE, the investigators used Brief Pain Inventory – Short Form (BPI-SF) and the Functional Assessment of Cancer Therapy – Prostate (FACT-P) measures. For BPI-SF, Morgans presented data on the measure “worst pain in past 24 hours.”

Morgans reported that darolutamide delayed time to pain progression vs placebo, with a median time to pain progression of NE seen in the darolutamide arm (95% CI: NE-NE) vs 29.9 months (95% CI: 29.7-NE) in the placebo group (stratified HR 0.72; 95% CI: 0.54-0.96).

“When we consider in the darolutamide treatment group only the time to pain progression by PSA response, which we have heard repeatedly in this session is associated with disease control outcomes, we can see that patients who reached a PSA of less than 0.02 or less than 0.2 ng/mL at any time during their treatment had a longer time to pain progression when compared to patients with a PSA of greater than or equal to 0.2. I think this is a really critical thing for us to recognize—that our patient's quality of life intuitively, of course, is associated with disease control, but this is also helpful for us in clinical practice, so that we can encourage patients as their cancer appears to be better controlled, we expect for them to feel better,” Morgans said.

Regarding FACT-P, treatment with darolutamide was found to extend median time to deterioration of FACT-P total score by 5.1 months vs placebo (stratified HR 0.76; 95% CI: 0.61-0.64). Morgans noted particular improvement in the following FACT-P subscales:

• social/family well-being (HR 0.79; 95% CI: 0.64-0.68)

• functional well-being (HR 0.78; 95% CI: 0.63-0.96)

• prostate cancer (HR 0.82; 95% CI: 0.66-1.01)

• urinary symptoms (HR 0.78; 95% CI: 0.61-0.99)

Stratifying the results by PSA response in the darolutamide arm, Morgans reported that patients who had a PSA level of less than 0.02 ng/mL or less than 0.2 ng/mL any time had a longer time to HRQoL deterioration compared with patients with a PSA level of at least 0.2 ng/mL.

“Darolutamide confers a positive impact on health-related quality of life. It's actually the first and only androgen receptor antagonist to demonstrate clinically meaningful delays in pain progression and overall well-being, including those specific areas of social and family, well-being, functional well-being, and urinary symptoms. Health related quality of life benefits may be greatest in patients treated with darolutamide who had ultra-low PSA responses,” Morgans concluded.

REFERENCES

1. Morgans A, Haresh KP, Jievaltas M, et al. Health-related quality of life (HRQoL) outcomes with darolutamide in the phase 3 ARANOTE trial. J Clin Oncol. 2025;43(suppl 17):5004. doi:10.1200/JCO.2025.43.16_suppl.5004

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