Triplet therapy with darolutamide a potential new standard of care for mHSPC

Adding darolutamide to androgen-deprivation therapy (ADT) plus docetaxel significantly increases overall survival (OS) in patients with metastatic, hormone-sensitive prostate cancer (mHSPC), according to the ARASENS* trial presented at the ASCO GUCS 2022.

Compared with ADT plus docetaxel, the addition of darolutamide to the combination slashed the risk of death by 32.5 percent, with no increase in toxicity.

“Darolutamide in combination with ADT and docetaxel should become a standard of care for treatment of mHSPC,” said lead author Dr Matthew Smith of the Massachusetts General Hospital Cancer Center in Boston, Massachusetts, US.

Darolutamide, being a structurally distinct and highly potent androgen-receptor inhibitor, shows “low blood-brain barrier penetration and [thus] limited potential for clinically relevant drug-drug interactions,” he explained.

Benefits across the board

In the global, double-blind, phase III trial, 1,306 patients (median age 67 years; ≥70 percent ECOG PS** of 0) with mHSPC were randomized 1:1 to receive darolutamide 600 mg twice daily or placebo, both in addition to a combination therapy of ADT plus docetaxel. [GUCS 2022, abtract 13; N Engl J Med 2022;doi:10.1056/NEJMoa2119115]

The addition of darolutamide significantly prolonged OS compared with placebo (median, not estimable [NE] vs 48.9 months; hazard ratio [HR], 0.68; p<0.001). At 4 years, 62.7 percent of the patients in the darolutamide arm were still alive compared with 50.4 percent in the placebo arm.

The survival benefit with darolutamide was seen despite a large proportion of patients (75.6 percent) in the placebo arm who received subsequent life-prolonging therapies — the most common one abiraterone acetate (46.9 percent), followed by enzalutamide (27.5 percent), cabazitaxel (18.0 percent), and docetaxel (18.0 percent).

OS remained longer in patients treated with darolutamide than with placebo when the analysis was stratified by metastatic stage at initial diagnosis (HR, 0.71, 95 percent confidence interval [CI], 0.59-0.85 for de novo metastatic disease; HR, 0.61, 95 percent CI, 0.35-1.05 for recurrent metastatic disease).

Moreover, the survival benefit with darolutamide was consistent across subgroups, regardless of the age, race, extent of disease, ECOG PS, PSA, ALP**, and Gleason score at baseline.

In addition, darolutamide also led to significant improvements in multiple key secondary endpoints, which included delaying the time to castration-resistant prostate cancer (median, NE vs 19.1 months, HR, 0.36; p<0.001), time to first symptomatic skeletal event (median, NE for both; HR, 0.71; p=0.02), and time to first subsequent antineoplastic therapy (median, NE vs 25.3 months; HR, 0.39; p<0.001).

Pain progression also occurred later in the darolutamide arm vs the placebo arm (median, NE vs 27.5 months; HR, 0.79; p=0.01).

“The combination did not result in more toxic effects than did the combination of ADT and docetaxel alone,” reported Smith and co-authors. “The incidence, severity, and nature of adverse events [AEs] were consistent with the established safety profiles of ADT and docetaxel.”

AEs occurred at similar rates between the darolutamide and the placebo groups, with the rates of the most common AEs^# being the highest during the overlapping treatment period with docetaxel. Grade 3/4 AEs were detected in 66.1 percent of patients in the darolutamide arm and 63.5 percent in the placebo arm — with neutropenia being the most common grade 3/4 AE (33.7 percent vs 34.2 percent).

Compelling, meaningful evidence

“This trial provided clear and compelling evidence that OS was significantly longer among patients who received combination therapy with darolutamide,” Smith highlighted.

Concurring with Smith was invited discussant Dr Elisabeth Heath from the Karmanos Cancer Institute in in Detroit, Michigan, US, who described the OS improvement as “very meaningful”.

Having witnessed the evolution of mHSPC treatment from single-agent ADT to the incorporation of a second drug and now a third, Heath commented that the findings showed “triplet therapy is here for consideration.”

Nonetheless, she also noted that many mHSPC patients are not even receiving the recommended doublet therapy in real world and suggested raising awareness and more education on the role of treatment intensification in improving survival of mHSPC patients.

 

*ARASENS: ODM-201 in addition to standard ADT and docetaxel in metastatic castration sensitive prostate cancer

**ECOG PS: Eastern Cooperative Oncology Group performance status

***PSA: Prostate-specific antigen; ALP: alkaline phosphatase

^#occurring in ≥10 percent of patients