Darolutamide Plus ADT Improves rPFS in mHSPC

The addition of darolutamide (Nubeqa) to androgen deprivation therapy (ADT) significantly enhanced radiographic progression-free survival (rPFS) comapred with ADT alone in patients with metastatic hormone-sensitive prostate cancer (mHSPC), according to data from the phase 3 ARANOTE trial (NCT04736199) presented at the 2024 ESMO Congress.

Compared with ADT alone, the addition of the androgen receptor pathway inhibitor (ARPI) darolutamide reduced the risk of radiographical progression or death by 46% (HR, 0.54; 95% CI, 0.41-0.71; P < .0001) and demonstrated a favorable safety profile in the phase 3 ARANOTE trial (NCT04736199).

“Darolutamide, ADT, plus docetaxel is already a standard of care for men with mHSPC and ARASENS [NCT02799602] shows that darolutamide plus ADT plus docetaxel had a favorable efficacy and safety profile compared with ADT plus docetaxel in these patients,” explained Fred Saad, MD, FRCS, professor and chairman of urology and director of genitourinary oncology at the University of Montreal Hospital Center in Canada, in his presentation. “ARANOTE was designed to evaluate the role of darolutamide [plus] ADT without docetaxel to hopefully provide a new treatment option for men with mHSPC.”

Despite the ARASENS trial establishing the efficacy of ARPI, ADT, and chemotherapy, it was only compared with ADT plus docetaxel, and darolutamide plus ADT had not been compared with ADT alone, leading to the design of the global, randomized, double-blind placebo-controlled ARANOTE trial to determine if this combination can be a treatment option without chemotherapy.

A total of 669 patients were randomly assigned on a 2:1 basis to receive darolutamide 600 mg twice daily plus ADT (n = 446) or placebo plus ADT (n = 223). They must have had metastatic disease confirmed by conventional imaging or soft tissue/visceral metastases on CT or MRI assessed by central review and ECOG performance status of 0, 1, or 2. They were stratified by presence or absence of visceral metastases and prior local therapy. The primary end point was rPFS by central blinded review, with secondary end points including overall survival, time to prostate-specific antigen (PSA) progression, and safety.

Baseline characteristics and disease characteristics were broadly similar across the arms; Saad highlighted the approximately 30% of the population who were Asian and 10% who were Black, which enabled these groups to be studied more closely. In the darolutamide group, 71.1% had de novo metastatic disease compared with 75.3% in the ADT alone group. Visceral disease was present in 11.9% and 12.1% of each respective arm, and 17.9% of each arm had prior local therapy.

Primary and Secondary Efficacy End Points

At data cutoff of June 7, 2024, median follow-up was 25.3 months for the darolutamide group and 25.0 months for the placebo group. The median rPFS for darolutamide plus ADT was not reached (95% CI, not reached-not reached [NR]) compared with 25.0 months for placebo plus ADT (95% CI, 19.0-NR). At 24 months, the rate of rPFS was 70.3% for the darolutamide group vs 52.1% for the placebo group.

The rPFS benefit with darolutamide was consistent across all analyzed subgroups. For patients with low disease volume, the HR was 0.30 (95% CI, 0.15-0.60) compared with an HR of 0.60 for those with high-volume disease (95% CI, 0.44-0.80). Those with prior local therapy had an HR of 0.34 (95% CI, 0.17-0.66) whereas those with no prior local therapy had an HR of 0.59 (95% CI, 0.44-0.79).

Although OS was not mature and was not reached in both arms, the stratified HR was 0.81 (95% CI, 0.59-1.11) favoring darolutamide. Adding darolutamide also showed a benefit across other secondary end points including time to metastatic castration-resistant prostate cancer (HR, 0.40; 95% CI, 0.32-0.51), time to PSA progression (HR, 0.31; 95% CI, 0.23-0.41), time to initiation of subsequent systemic therapy (HR, 0.40; 95% CI, 0.29-0.56), and time to pain progression (HR, 0.72; 95% CI, 0.54-0.96). It also led to 62.6% of patients with PSA less than 0.2 ng/mL at any time during treatment, compared with only 18.5% in the placebo group.

Safety of Adding Darolutamide

The median treatment duration was 24.2 months in the darolutamide group compared with 17.3 months for the placebo group. Incidence of treatment-emergent adverse events (TEAEs) was similar between the arms, with 91.0% any-grade and 30.8% grade 3 or 4 TEAEs with darolutamide plus ADT and 90.0% any-grade and 30.3% grade 3 or 4 with ADT plus placebo. There was a rate of 4.7% grade 5 TEAEs in the darolutamide group vs 5.4% for the placebo group. Serious TEAEs occurred at a rate of 23.6% in the darolutamide group vs 23.5% in the placebo group, and 6.1% discontinued treatment due to TEAEs in the darolutamide group, a lower rate than the 9.0% in the placebo group.

When looking at TEAEs associated with ARPIs in particular, they were still similar across the groups. Fatigue, mental impairment disorder, hypertension, cardiac arrythmias, coronary artery disorders, heart failure, falls, bone fracture, vasodilation and flushing, diabetes and hyperglycemia, and rash all occurred in fewer than 10% of patients in either arm, and exposure-adjusted incidence rate per 100 patient years was also similar in the darolutamide and placebo groups.

“In conclusion, darolutamide and ADT significantly improved rPFS in patients with mHSPC, showed a benefit across all secondary endpoints, [and] had a favorable safety profile, confirming previous studies using darolutamide,” said Saad. “We believe that darolutamide and ADT, without the need of docetaxel, could become an additional standard of care for mHSPC.”

Reference:

1. 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. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract LBA68.