Addition of Darolutamide May Augment Standard Treatment for Localized, Very High-Risk Prostate Cancer

Ray McDermott, MB, BCh, BAO, PhD, MBA, FRCPI, discusses the benefit achieved with standard-of-care radiation therapy plus androgen deprivation therapy with a luteinising hormone-releasing hormone analogue.

Despite the benefit achieved with standard-of-care radiation therapy plus androgen deprivation therapy (ADT) with a luteinising hormone-releasing hormone analogue, 15% of patients with very high-risk, localized prostate cancer still go on to develop incurable distant metastases within 5 years underscoring a need to augment this approach, according to Ray McDermott, MB, BCh, BAO, PhD, MBA, FRCPI.

The ongoing phase 3 DASL-HiCaP trial (NCT04136353), presented during the 2020 ESMO Virtual Meeting, may address this challenge, as investigators are evaluating the efficacy of adding darolutamide (Nubeqa) to ADT and radiation treatment either as a primary definitive therapy or adjuvant therapy in this patient population.

“Patients with high-risk prostate cancer are those whose prostate-specific antigen [PSA] levels have gone up after undergoing a radical prostatectomy,” said McDermott. “We must find ways to leverage treatment options for these patients [in order to] prevent disease recurrence. I encourage patients to look for centers where this study is open to see whether they’re eligible to participate.”

In the double-blind, placebo-controlled phase 3 trial, a total of 1100 patients will be stratified based on whether they are receiving adjuvant docetaxel, have pelvic nodal involvement, or they have undergone a radical prostatectomy. Participants will be randomized 1:1 to receive either 600 mg of darolutamide or placebo twice daily for the duration of 96 weeks. They will also receive a luteinising hormone releasing hormone analogue for 96 weeks and radiation therapy on weeks 8-24 following randomization.

Despite delays caused by the coronavirus disease 2019 (COVID-19) pandemic, investigators plan to open the trial at 100 sites across the United States, Canada, Ireland, the United Kingdom, Australia, and New Zealand.

In an interview with OncLive, McDermott, a clinical professor of medical oncology at the University College Dublin, discussed the key objective of the DASL-HiCaP trial in patients with very high-risk prostate cancer and the benefits of darolutamide compared with other novel antiandrogens that are available.

OncLive: What was the rationale for the DASL-HiCaP trial in patients with very high-risk prostate cancer?

McDermott: Two populations of patients [will be] included in this study. First, there are the patients who are being treated definitively with radiation and ADT for very high-risk prostate cancer. The second population of patients are those who have already had a radical prostatectomy and whose PSA levels have not dropped to 0; these patients are planned [to receive] salvage radiotherapy with hormones.

In both of those cases, with the current standard of care, a significant proportion [of patients] will still develop metastatic disease over the next 5 years. The [rationale] for this research is to evaluate the addition of darolutamide, which is a novel androgen receptor blocker, to see whether we can reduce the incidence of patients developing metastases over time.

What is the design of the trial? 

Notably, the study does not allow patients with metastatic disease to enroll, but those who have nodal involvement in their pelvis are permitted; that’s 1 of the stratification factors. Another factor is whether patients used adjuvant docetaxel; in some centers, this agent is used in this setting, as well. The other stratification factor is whether patients have undergone a radical prostatectomy. 

The study was originally designed in Australia, but will be conducted in the United States, Canada, Europe, and New Zealand. A total of 1100 patients will be randomized 1:1 to receive darolutamide for 96 weeks or placebo.

How might this research help to address the unmet needs still faced in these patients with very high-risk prostate cancer?

[In these] high-risk patients, specifically those whose PSA levels increased after undergoing a radical prostatectomy, we know that despite our best efforts and the use of ADT, many will still develop PSA recurrence. When patients recur, a large percentage will then develop metastases; this may lead to the prostate cancer ultimately taking the patient’s life. The ultimate goal of this study is to reduce the number of PSA relapses.

What are some of the benefits associated with darolutamide over other available antiandrogens?

One of the advantages with darolutamide compared with some of the other novel antiandrogen agents out there is that it doesn't cross the blood–brain barrier. One of the main adverse effects we observe with other antiandrogens is that they can increase the risk of falls; they can also affect cognition and memory. However, this does not seem to be the case with darolutamide. Patients are going to be on this medication for close to 2 years, which is a very important point. We don’t want to excessively interfere with our patients’ quality of life.

When might results from the trial be expected? Has the pandemic impacted accrual?

The study has only recently opened. Accrual began in March 2020, and as of August 2020, 30 patients had been enrolled to the trial. We will continue to accrue patients over the next few years, and we will report our findings in the future after accrual is completed.

We want to open this trial to different centers across the world, although the COVID-19 pandemic has delayed this. There will be an accrual period over the next 2 years and then a follow-up period.

One of the good things about prostate cancer is that if the disease is going to recur, it may happen later rather than straightaway. Therefore, the follow-up for this trial will probably take a number of years before the primary end point is determined.

Is there any other research in this space that you’re excited about and wanted to highlight?

The survival advantage with PARP inhibitors demonstrated in the PROfound study was very exciting. Although this is a smaller patient population, this trial emphasized the importance of testing patients to see whether they harbor any of these actionable mutations. [With these options], patients are living longer and are avoiding more toxic treatments like chemotherapy.


Niazi T, Williams S, Davis ID, et al. DASL-HiCaP: darolutamide augments standard therapy for localised very high-risk cancer of the prostate (ANZUP1801). A randomised phase III double-blind, placebo-controlled trial of adding darolutamide to androgen deprivation therapy and definitive or salvage radiation. Ann Oncol. 2020;31(suppl 4):S548-S549. doi:10.1016/j.annonc.2020.08.2088