ARANOTE: Darolutamide positively impacts HRQoL in men with mHSPC

Darolutamide demonstrated clinically meaningful delays in pain progression and deterioration of important patient-relevant health-related quality of life (HRQoL) outcomes vs placebo in men with metastatic hormone-sensitive prostate cancer (mHSPC), according to phase III ARANOTE trial findings presented at ASCO 2025. [ASCO 2025, abstract 5004]

Significant efficacy and favourable tolerability in a diverse population

“Darolutamide offers significant efficacy benefits and favourable tolerability for patients with mHSPC,” said presenter Dr Alicia Morgans of Dana-Faber Cancer Institute in Boston, Massachusetts, US.

The addition of darolutamide to androgen deprivation therapy (ADT) and docetaxel significantly improved survival and reduced the risk of death by 32.5 percent vs placebo (hazard ratio [HR], 0.68; 95 percent confidence interval [CI], 0.57–0.80; p<0.001) in the phase III ARASENS trial, which involved 1,306 patients with mHSPC. [N Engl J Med 2022;386:1132-1142]

In the phase III ARANOTE trial involving 669 patients with mHSPC, the addition of darolutamide to ADT reduced the risk of radiological progression or death by 46 percent vs placebo (HR, 0.54; 95 percent CI, 0.41–0.71; p<0.0001). The majority of patients did not experience grade ≥3 treatment-emergent adverse events (TEAEs) (darolutamide vs placebo, 64.5 vs 64.3 percent). Interestingly, TEAEs leading to discontinuation of study drug were reported in 6.1 percent of patients receiving darolutamide vs 9.0 percent of patients receiving placebo. [J Clin Oncol 2024;42:4271-4281]

“These studies provide an option to select treatment for mHSPC with or without docetaxel to meet patients’ individual needs or preferences,” noted Morgans.

In ARANOTE, patients’ median age was 70 years, median prostate-specific antigen (PSA) level was 21 ng/mL, and the majority were enrolled with de novo metastatic disease (darolutamide arm, 71.1 percent; placebo arm, 75.3 percent), which was often high-volume (70.6 and 70.4 percent, respectively). Visceral metastases were present in approximately 12 percent of patients and 18 percent of patients had received prior local therapy. Approximately half of the patients had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, while the other half had an ECOG PS of 1–2.

“Importantly, this study had sites outsides of the US, with approximately 30 percent of patients enrolled from sites across Asia and 30 percent from sites in Latin America,” highlighted Morgans.

Patients’ concerns beyond survival

“Most patients come to the clinic because they wish to live longer, but they also have other concerns and considerations. They want to control the PSA level, which stresses them out. They want to avoid TEAEs at all costs, if that is possible. They want to minimize pain and other symptoms that may prevent them from doing what they wish. They want to maintain independence and their ability to support their families as they have before diagnosis, and they certainly want to maintain well-being and quality of life [QoL] as they engage in things that really make them happy,” shared Morgans. 

To assess patients’ experience of treatment, ARANOTE employed patient-reported outcome measures. The Brief Pain Inventory-Short Form was used to assess the worst pain in the past 24 hours. Functional Assessment of Cancer Therapy-Prostate (FACT-P) total score was also used, which includes multiple domains: physical well-being (assessing energy and symptoms, side effects), social/family well-being (feeling close to/supported by family/friends), emotional well-being (feeling sad or nervous, losing hope, worrying), functional well-being (ability to work/sleep, enjoying life), prostate cancer (bowel/urinary difficulties).

Delay in pain progression and FACT-P deterioration

The secondary endpoint of median time to pain progression in the ARANOTE trial, defined as time from randomization to confirmed increase of ≥2 points in worst pain score over nadir or initiation of opioid treatment for ≥7 days, was not reached in the darolutamide arm and was 29.9 months in the placebo arm (stratified HR, 0.72; 95 percent CI, 0.54–0.96).

A post hoc analysis of the darolutamide group’s findings showed that patients reaching a PSA level of <0.02 ng/mL (median time, not estimable [NE]) or 0.02–<0.2 ng/mL (median time, NE) at any time had longer time to pain progression vs patients whose PSA level was ≥0.2 ng/mL (median time, 17.9 months). “[These findings] are helpful to us in clinical practice, so that we can encourage patients that as their cancer appears to be better controlled, we expect them to feel better,” commented Morgans.

Darolutamide extended the prespecified exploratory endpoint of median time to first deterioration in FACT-P total score of ≥10 points by 5.1 months vs placebo (16.6 vs 11.5 months; stratified HR, 0.76; 95 percent CI, 0.61–0.94). “This is possibly driven by improvements that are most prominent in social and family well-being, functional well-being, prostate cancer concerns, and urinary symptoms [subscale scores],” noted Morgans.

In post hoc analysis, patients in the darolutamide group with a PSA level of <0.02 ng/mL (median time, 19.4 months) or 0.02–<0.2 ng/mL (median time, 22.3 months) at any time had longer time to HRQoL deterioration vs patients with PSA level ≥0.2 ng/mL (median time, 11.3 months).

ARANOTE HRQoL conclusions

“Darolutamide confers a positive impact on HRQoL. It is the first and only androgen receptor antagonist to demonstrate clinically meaningful delays in pain progression and overall well-being, including the specific areas of social and family well-being, functional well-being, and urinary symptoms,” stated Morgans.

“These HRQoL benefits may be the greatest in patients treated with darolutamide who have ultra-low PSA,” she added.