Darolutamide Plus Docetaxel in Metastatic Hormone-Sensitive Prostate Cancer

Metastatic, hormone-sensitive prostate cancer is treated as standard by adding either docetaxel chemotherapy or an androgen receptor pathway inhibitor to testosterone-suppressing therapy. Adding docetaxel or an androgen receptor pathway inhibitor (abiraterone, enzalutamide or apalutamide) to testosterone-suppressing therapy is known to result in significantly better survival than testosterone suppression alone.

While adding docetaxel alone or an androgen receptor inhibitor alone to androgen deprivation therapy improves survival, the effect of adding both docetaxel and an androgen receptor inhibitor simultaneously had been unknown.

At the 2022 ASCO Genitourinary Cancers Symposium, a study presented and reported in The New England Journal of Medicine was published simultaneously . Conducted by Dr. Matthew R. Smith and colleagues, it examined men with metastatic, hormone-sensitive prostate cancer (that is, newly diagnosed advanced disease without previous treatment). Adding both docetaxel and the androgen receptor inhibitor darolutamide to testosterone-suppressing therapy significantly improved overall survival compared with testosterone-suppressing therapy plus docetaxel alone.

What Is Darolutamide?

Darolutamide (brand name Nubeqa) is a cancer drug that received its first and only FDA approval in 2019 for patients whose prostate cancer had not yet metastasized but had developed resistance to hormone suppression. It is a structurally distinct androgen receptor inhibitor with low blood-brain barrier penetration and a relatively lower risk of drug-drug interactions.

Below is a simple illustration of the mechanisms of newer-generation prostate cancer drugs abiraterone, enzalutamide, apalutamide and darolutamide. Abiraterone inhibits enzymes involved in androgen formation, while androgen receptor blockers such as darolutamide prevent androgens from binding to their receptors, entering the nucleus and binding to DNA in the nucleus.

The ARASENS Study

The international, randomized, double-blind, placebo-controlled phase III ARASENS study by Dr. Smith and colleagues enrolled 1306 patients. The 651 patients in the experimental arm received darolutamide in addition to hormone suppression and docetaxel, while the 655 patients in the control group received placebo in addition to standard treatment. Adding darolutamide to standard treatment significantly increased survival. This survival improvement was similar to the results of the phase III PEACE-1 study, in which abiraterone had previously been added to hormone suppression plus docetaxel.

In their published report, the researchers stated that darolutamide also reduced the risk of death by 32.5%.

Figure description: Median survival was not reached in the darolutamide arm because more than half of the patients remained alive; it was 48.9 months in the standard-treatment arm. KT: chemotherapy: ADT: androgen deprivation therapy

No greater difference in toxic effects was observed between the triple and double combinations. In both the abiraterone and darolutamide studies, the frequency of common androgen receptor inhibitor-related side effects observed compared with the placebo groups was at most 2%.

Most patients enrolled in the study had bone metastases, visceral (internal organ) metastases or both at initial diagnosis. Information on benefit-risk assessment is therefore limited for patients with recurrent hormone-sensitive prostate cancer, node-only metastases or both, who have a better prognosis.

In conclusion, this study by Dr. Smith and colleagues supports using darolutamide, testosterone-suppressing therapy and docetaxel in patients with metastatic, hormone-sensitive prostate cancer. The combination increased overall survival and produced improvements without increasing side effects.