Darolutamide With Radiation Therapy Under Clinical Trial Investigation in Intermediate-Risk Prostate Cancer

Martin T. King, MD, PhD

Martin T. King, MD, PhD

For the treatment of intermediate-risk prostate cancer, the standard-of-care is external beam radiation (EBRT), which is administered with or without 4 to 6 months of androgen deprivation therapy (ADT). According to Martin T. King, MD, PhD, this treatment is associated with delayed testosterone recovery and causes prolonged erectile dysfunction in these patients, thereby creating a need for alternative treatment options.

King and colleagues hypothesized that using the antiandrogen agent darolutamide (Nubeqa) in combination with radiation therapy (RT) would act as a surrogate for ADT plus RT by achieving long-term disease control and preventing erectile dysfunction in patients.

The investigators are setting out to prove their hypothesis in the phase IIb multicenter, randomized-controlled INTREPId trial (NCT04025372). The ongoing study aims to enroll 220 participants with intermediate-risk prostate cancer to assess the percentage of patients with a prostate-specific antigen (PSA) nadir ≤0.5, the primary end point of the study. The secondary end points include the percentage of patients with good erectile function, PSA progression-free survival, metastasis-free survival, cause-specific survival, rate of toxicity, and quality of life.

Patients in the study will be randomized to receive either 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. The target completion date of the study is September of 2027.

In an interview withTargeted Oncology, King, a radiation oncologist at the Brigham and Women’s Hospital, discusses INTREPId following his poster presentation of the trial design at the 2020 Genitourinary Cancer Symposium (GU 2020). He also discusses other another promising studies being presented at the conference.

TARGETED ONCOLOGY: In general, what are outcomes like for patients with prostate cancer who are treated with EBRT and/or ADT?

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.

TARGETED ONCOLOGY:What data have been reported on darolutamidethat support its use in this patient population?

King: Darolutamide has been shown to be effective in many 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 anti-androgen 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.

TARGETED ONCOLOGY: What is the role of genomic testing in prostate cancer?

King: 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.

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

King: 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.

TARGETED ONCOLOGY: Are there any prostate cancer data coming out of GU 2020 that you’re excited to see?

King: 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.

Reference:

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).