In advanced prostate cancer, androgen deprivation therapy (ADT) has been a mainstay of treatment for more than fifty years. The details of ADT are discussed here if you'd like to learn more. In the past decade or so, physicians who treat advanced prostate cancer have come to understand that, in a variety of clinical scenarios, ADT alone is not enough. As a result, other treatments are now being added to ADT in so called “treatment intensification”. While chemotherapy was the first to be added to ADT, so-called novel hormonal therapies (NHTs; also known as androgen receptor-axis-targeted therapies (ARATs)) are more commonly used for most patients today. While ADT effectively decreases the testosterone within the body that drives prostate cancer growth, the success of these treatments clearly shows that targeting of testosterone-driven pathways has benefit in advanced prostate cancer.

Darolutamide was the last of the approved NHTs to become available. Like enzalutamide and apalutamide, it acts to block the action of testosterone by affecting the androgen receptor. It blocks the androgen receptor’s ability to carry out its functions in a variety of ways including blocking its movement within the cell, blocking its ability to interact with DNA, and blocking its ability to create signals within the cell. In this mechanism, darolutamide acts as a more potent version of prior anti-androgens such as bicalutamide.

In contrast to apalutamide and enzalutamide, darolutamide cannot get access to the brain so it has fewer brain-related side effects.

Who might be prescribed Darolutamide?

Darolutamide is approved, and has demonstrated survival benefits, for men with advanced prostate cancer in two difference scenarios. First, in men with non-metastatic castration resistant prostate cancer (nmCPRC; in which in darolutamide will be started after the PSA is going up even though the testosterone is low while on ADT and there are no sites of metastasis on imaging), the ARAMIS study showed the using darolutamide reduced the risk of men developing metastases by 59%. Further, even though men who developed metastases received additional treatment at that time, starting darolutamide early before the metastases developed reduced the risk of death by 31%.

Darolutamide has also, very recently, been approved for men with metastatic castration sensitive prostate cancer (mCSPC; where darolutamide will be started concurrently or shortly after ADT) based on the ARASENS study. In this study, the authors compared the combination of darolutamide with docetaxel chemotherapy and ADT to docetaxel chemotherapy and ADT. This study showed that the so-called “triplet” combination with darolutamide, chemotherapy, and ADT reduced the chance of death by more than 32% compared to chemotherapy and ADT. This triplet approach was approved by the FDA on August 5, 2022.

Patients who should not take Darolutamide

There are limited reasons why patients should not take darolutamide. Patients with an allergy or hypersensitivity to darolutamide should not receive it. As always, let your physician know if you have heart, liver, or kidney problems. Your doctor may opt to give you a lower dose of darolutamide in some of these circumstances. Importantly, unlike apalutamide and enzalutamide, men with a history of seizures or a stroke in the past may safely take darolutamide.

Instructions for taking Darolutamide

Darolutamide is prescribed as two tablets to be taken two times each day. These should be taken at the same time each day and may be taken either with or without food.

Darolutamide may have effects on other medications that you are taking. As your physician discusses treatment options for advanced prostate cancer, ensure that they are aware of all of the other medications that you are taking. Further, a cancer pharmacist can be very helpful in ensuring that there are not harmful interactions between taking multiple medications.

Side effects of Darolutamide

There are both common (and often relatively mild) and uncommon (and sometimes severe) side effects. Among the more common side effects are significant fatigue (tiredness), pain in your arms or legs, and rash. Darolutamide may also increase the chance of heart disease and may have effects on blood tests for liver function. Importantly, darolutamide does not increase the risk of seizures, falls, or fractures (broken bones), unlike apalutamide and enzalutamide.

As always, the articles on this site should not constitute specific medical advice. Discuss the specifics of your clinical situation and your treatment options with your physician.

Zachary Klaassen, MD, MSc
Urologic Oncologist, Georgia Cancer Center, Augusta University, Augusta, GA, USA