Researchers Building on Darolutamide Success in Prostate Cancer

Martin T. King, MD, PhD

The phase III ARAMIS trial showed that darolutamide (Nubeqa) plus androgen deprivation therapy (ADT) significantly improved overall survival (OS) compared with placebo plus ADT in patients with nonmetastatic castration-resistant prostate cancer.

Investigators for the phase II INTREPId trial (NCT04025372) are now trying to determine whether darolutamide can be successfully substituted for ADT for use in combination with radiation therapy (RT) for patients with intermediate-risk prostate cancer. The researchers hope to improve patients’ quality of life by replacing ADT, as the treatment is associated with several adverse events, including erectile dysfunction.

The INTREPId trial has a target enrollment of 220 patients who will be randomized to oral bicalutamide daily with a gonadotropin-releasing hormone agonist as prescribed and RT starting 8 to 12 weeks after ADT or oral darolutamide twice daily plus RT.

In an interview with OncLive during the 2020 Genitourinary Cancers Symposium, study investigator and radiation oncologist Martin T. King, MD, PhD, Brigham and Women's Hospital, discussed the INTREPId trial exploring darolutamide plus RT in patients with prostate cancer.

OncLive: What was the rationale for this trial?

King: Many of the patients who are diagnosed with prostate cancer are concerned about side effects, which are an important indicator of their quality of life, particularly in the case of erectile dysfunction.

The reason why we thought about doing this trial is that many patients with intermediate-risk disease, especially with the more unbearable subtypes, are recommended hormone therapy and EBRT. The hormone therapy can cause a lot of adverse events, including erectile dysfunction.

[Our goal was to determine if we] can substitute that hormone therapy with a new androgen therapy called darolutamide to preserve their quality of life while maintaining the ability to have long term control.

What previously reported darolutamide data support this study?

Darolutamide has been shown to be effective in many patients who have a recurrence or for whom the hormone therapy doesn’t work anymore. The ARAMIS trial recently showed that the addition of darolutamide to androgen deprivation therapy improved metastasis-free survival. Additionally, darolutamide, like many of the secondary antiandrogen therapies, causes less erectile dysfunction.

This will be one of the first trials to test whether they can actually substitute hormone therapy or ADT with darolutamide.

What is the role of genomic testing in prostate cancer, and how did you incorporate that into the study design?

At this point, genomic classifiers can determine prognostic outcomes. For example, patients with more gene mutations are more likely to have adverse biology [associated with a poor prognosis of] their prostate cancer.

There are less data on how genomic classifiers can impact clinical practice.

One of the best ways to learn how genomic classifiers should be incorporating in clinical practice would be to incorporate them into a clinical trial. In a trial design such as this, we’ll be able to see if patients with high genomic risks can safely undergo hormonal de-escalation with darolutamide alone; or [determine if it is] only safe for patients with low- or intermediate-risk disease. We should be able to get at least some signal on the safety of ADT plus darolutamide in patients with high-risk or low/intermediate-risk disease.

If this trial is positive, how do you think that will impact the treatment landscape for prostate cancer?

If the trial is positive, many patients with this disease will be able to get appropriate treatment with ADT and darolutamide, which is the ultimate goal.

Another unique aspect of the trial is that all patients will get a genomic classification score. The genomic classifier will tell us what the patient’s risk of disease progression is. Patients that have a higher risk score get more extreme radiation dose escalation.

Hopefully, we will be able to escalate the radiation for men with the most aggressive types of cancers while de-escalating the hormone therapy part.

What prostate cancer data shared at this meeting are you excited about?

For patients with hormone-sensitive prostate cancer, there have been many positive trials [dedicated to] trying to determine whether chemotherapy works versus abiraterone (Zytiga), enzalutamide (Xtandi), and apalutamide (Erleada). They have all be shown to work.

There was an interesting study, which compares the quality of life for patients who had abiraterone first or patients who had docetaxel first. What the results seem to show is that there was a better quality of life for patients who were treated with abiraterone rather than chemotherapy. The study is important because quality of life is a vital aspect in the treatment of prostate cancer, especially since patients live so long. It’s good to see that these androgen receptor agents are still able to preserve the quality of life over main applications. There are some parallels with that study in our current trial.

King MT, Wise DR, Scala LM, et al. INTREPId (Intermediate Risk Erection Preservation Trial): a randomized trial of radiation therapy and darolutamide for prostate cancer. J Clin Oncol. 2020;38(suppl 6; abstr TPS384).