The combination of Nubeqa (darolutamide) plus androgen deprivation therapy (ADT; reduces the amount of testosterone in the body) significantly improved radiographical progression-free survival (PFS; the length of time during and after treatment when a patient with cancer lives without the disease worsening) in patients with metastatic hormone-sensitive (still responds to hormone therapy) prostate cancer (mHSPC), according to results presented at the 2024 ESMO Congress.
Compared with ADT alone, the addition of the androgen receptor pathway inhibitor (ARPI; blocks activity of androgen receptor, a protein that aids cancer growth) Nubeqa reduced the risk of radiographical progression or death by 46% and demonstrated low safety risks in the phase 3 ARANOTE trial.
“[Nubeqa], ADT, plus docetaxel is already a standard of care for men with mHSPC and ARASENS shows that [Nubeqa] plus ADT plus docetaxel had a favorable efficacy and safety profile compared with ADT plus docetaxel in these patients,” explained Dr. Fred Saad, 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 [Nubeqa] [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 Nubeqa plus ADT had not been compared with ADT alone, leading to the ARANOTE trial to determine if this combination can be a treatment option without chemotherapy.
A total of 669 patients were randomly assigned to receive Nubeqa 600 milligrams twice daily plus ADT (446 patients) or placebo plus ADT (223 patients). 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 (fully active), 1 (limited activity), or 2 (poor activity). They were stratified by presence or absence of visceral metastases (spreading of cancer to internal organs) and prior local therapy. The primary focus was radiographical PFS (rPFS) by central blinded review, with secondary focuses including overall survival (OS; time from the start of treatment when a patient with cancer is still alive), time to prostate-specific antigen (PSA; time it takes for PSA levels to rise after treatment) progression and safety.
Baseline characteristics and disease characteristics were broadly similar across the groups; 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 Nubeqa 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 group and 17.9% of each group 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 Nubeqa group and 25 months for the placebo group. The median rPFS for Nubeqa plus ADT was not reached, meaning less than half of patients did not show disease progression, compared with 25 months for placebo plus ADT. At 24 months, the rate of rPFS was 70.3% for the Nubeqa group versus 52.1% for the placebo group.
The rPFS benefit with Nubeqa was consistent across all analyzed subgroups. For patients with low disease volume, the hazard ratio (HR; a statistical measure comparing the risk of an event between two groups) was 0.3 compared with an HR of 0.6 for those with high-volume disease. Those with prior local therapy had an HR of 0.34 whereas those with no prior local therapy had an HR of 0.59.
Although OS was not mature and was not reached in both groups, the stratified HR was 0.81 favoring Nubeqa. Adding Nubeqa also showed a benefit across other secondary focuses including time to metastatic castration-resistant prostate cancer, time to PSA progression, time to initiation of subsequent systemic therapy and time to pain progression. It also led to 62.6% of patients with PSA less than 0.2 nanograms/milliliter at any time during treatment, compared with only 18.5% in the placebo group.
Safety of Adding Nubeqa
The median treatment duration was 24.2 months in the Nubeqa group compared with 17.3 months for the placebo group. Incidence of treatment-emergent adverse events (TEAEs; treatment induced side effects) was similar between the groups, with 91% any-grade and 30.8% grade 3 (severe) or 4 (life threatening) TEAEs with Nubeqa plus ADT and 90% any-grade and 30.3% grade 3 or 4 with ADT plus placebo. There was a rate of 4.7% grade 5 (fatal) TEAEs in the Nubeqa group versus 5.4% for the placebo group. Serious TEAEs occurred at a rate of 23.6% in the Nubeqa group versus 23.5% in the placebo group and 6.1% discontinued treatment due to TEAEs in the Nubeqa group, a lower rate than the 9% in the placebo group.
When looking at TEAEs associated with ARPIs in particular, they were similar across the groups. Fatigue, mental impairment disorder, hypertension, cardiac arrythmias, coronary artery disorders, heart failure, falls, bone fracture, vasodilation (the widening of blood vessels) and flushing, diabetes and hyperglycemia, and rash all occurred in fewer than 10% of patients in either group and exposure-adjusted incidence rate per 100 patient years was also similar in the Nubeqa and placebo groups.
“[Nubeqa] 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 [Nubeqa],” said Saad. “We believe that Nubeqa and ADT, without the need of docetaxel, could become an additional standard of care for mHSPC.”
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