Darolutamide plus ADT shows rPFS benefit in mHSPC

Results of the phase 3 ARANOTE study (NCT04736199) indicate that combination treatment with darolutamide (Nubeqa) plus androgen deprivation therapy (ADT) is associated with a significant reduction in the risk of radiological progression or death in men with metastatic hormone-sensitive prostate cancer.

The data were presented at the 2024 European Society for Medical Oncology Congress in Barcelona, Spain and published in The Journal of Clinical Oncology.^1,2

Fred Saad, CQ, MD, FRCS, FCAHS

“Darolutamide plus ADT plus docetaxel is already a standard of care for men with metastatic hormone-sensitive prostate cancer, and ARASENS [NCT02799602] showed that darolutamide plus ADT plus docetaxel had a favorable efficacy and safety profile compared to ADT plus docetaxel in these patients.³ ARANOTE was designed to evaluate the role of darolutamide plus ADT without docetaxel to hopefully provide a new treatment option for men with metastatic hormone-sensitive prostate cancer,” said presenting author Fred Saad, CQ, MD, FRCS, FCAHS, director of Prostate Cancer Research, Montreal Cancer Institute, CRCHUM and professor of surgery at the University of Montreal, Quebec, Canada.

ARANOTE is a global, randomized double-blind, placebo-controlled study that enrolled 669 men with metastatic hormone-sensitive prostate cancer with ECOG Performance Status of 0-2. Patients were randomly assigned 2:1 to receive darolutamide, 600 mg BID plus ADT (n=446) or to placebo plus ADT (n=223). The primary end point of the study was radiological progression-free survival (rPFS) by blinded central review; secondary end points included overall survival, time to initiation of subsequent anticancer therapy, time to metastatic castration-resistant prostate cancer, time to prostate-specific antigen (PSA) progression, rates of undetectable PSA (< 0.2 ng/mL), time to pain progression, and safety.

Baseline demographics and disease characteristics were similar between the darolutamide and placebo/ADT arms. Saad noted that 32.3% of patients in the darolutamide arm were Asian, and 9.2% were Black, and that 29.1% of patients in the placebo/ADT arm were Asian and 10.8% were Black. Median PSA level was 21.4 ng/mL in the darolutamide arm vs 21.2 ng/mL in the placebo/ADT arm.

According to the authors, “darolutamide significantly reduced the risk of radiological progression or death by 46%” (HR=0.54, 95% CI, 0.41-0.71, P < .0001).

“Patients in the darolutamide arm did not reach first rPFS median, but at 24 months, 70[.3]% had not progressed vs 52[.1]% in the placebo/ADT arm,” Saad reported.

Saad added that all subgroups derived benefit from treatment with darolutamide/ADT. The HR for high-volume disease was 0.60 (95% CI, 0.44-0.80), and the HR for low-volume disease was 0.30 (0.15-0.60).

Treatment-emergent adverse event (TEAE) incidence was found to be similar between the 2 groups, with rates of TEAEs leading to permanent discontinuation of study drug of 6.1% of patients in the darolutamide arm and 9.0% of patients in the placebo/ADT arm.

Discussing secondary end points, Saad said, “The secondary end points, all favored, again, darolutamide. Overall survival, with only about 24 months of follow-up, is still immature and not reached in either arm. But importantly, time to metastatic CRPC…was improved, with a hazard ratio of 0.40 [95% CI, 0.32-0.51], so a 60% reduction in terms of time to mCRPC. And in terms of time to pain progression, there was a 28% advantage in the patients getting darolutamide over placebo.”

In patients receiving darolutamide, 62.6% of patients achieved a PSA level of < 0.2 ng/mL at any time during treatment vs 18.5% of patients in the placebo/ADT arm. In addition, time to PSA progression was improved by 69% (HR=0.31, 95% CI, 0.23-0.42) in patients receiving darolutamide vs placebo/ADT.

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

REFERENCES

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 European Society for Medical Oncology Annual Congress. September 13-17, 2024. Barcelona, Spain. Abstract LBA68. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2024_abstracts/LBA68.html.pdf

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. 2024 Sep 16:JCO2401798. doi:10.1200/JCO-24-01798

3. Smith MR, Hussain MH, Saad F, et al. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med. 2022;386(12):1132-1142. doi:10.1056/NEJMoa2119115