Third or Fourth Place in the Race? No Problem – The Case for More Trials Using Darolutamide for Patients with Prostate Cancer

Darolutamide first received regulatory approval for patients with non-metastatic (M0) castration-resistant prostate cancer based on the results of the ARAMIS trial.¹  Although apalutamide and enzalutamide were regulatory approved prior to darolutamide, all three agents were successful in demonstrating both metastasis-free and overall survival benefit in their respective randomized phase 3 trials over placebo.^1-3

In the metastatic castration-sensitive prostate cancer disease state, we have also seen overall survival benefit with many single agent additions to androgen deprivation therapy; this includes docetaxel chemotherapy and multiple androgen pathway inhibitors like abiraterone, enzalutamide, and apalutamide.^5-10

The latest advancement in treatment intensification for metastatic castration-sensitive prostate cancer is triple combination therapy, combining androgen deprivation therapy plus docetaxel with either abiraterone or docetaxel.  In the PEACE-1 trial, superior outcomes were seen in de novo metastatic castration-sensitive prostate cancer patients who received androgen deprivation therapy, docetaxel and abiraterone compared to those who received androgen deprivation therapy and docetaxel: radiographic progression free survival (median 4.5 vs. 2.0 years; HR 0.50, 95% CI 0.40-0.62, p<0.0001) and overall survival (median Not evaluable vs. 4.4 years; HR 0.75, 95% CI 0.59-0.95, p=0.017).¹¹

The ARASENS trial enrolled patients eligible for docetaxel to androgen deprivation therapy plus docetaxel with randomization to darolutamide or placebo.¹²  Overall survival was superior for those patients who received darolutamide (HR 0.68; 95% CI 0.57-0.80; p<0.001).  Although the ARASENS trial enrolled anyone deemed fit for docetaxel, determined by the investigator and patient, it turned out that 86.1% of patients enrolled had de novo metastatic prostate cancer.  The de novo metastatic prostate cancer patients are generally deemed to be a patient population with a worse prognosis and more aggressive disease.  Recently, regulatory approval was granted for the use of darolutamide with androgen deprivation therapy and docetaxel.¹³  This FDA label allows for darolutamide to be started first and docetaxel to be initiated up to 12 weeks later.  However, there is no approval for darolutamide alone for patients with metastatic castration-sensitive prostate cancer.

Although darolutamide has approvals for both M0 castration-resistant prostate cancer and as part of triple combination therapy for metastatic castration-sensitive prostate cancer, there are some unique properties to this agent that warrant consideration for use.  For example, compared to other pure androgen receptor antagonists, the biochemical structure of darolutamide is distinct.¹⁴  There is little penetration through the blood brain barrier, resulting in theoretically lower seizure risk and neurocognitive effects.  Unlike the trials with other androgen receptor antagonists, trials studying darolutamide did not exclude patients with a seizure history or significant risk of seizures.  There is also a general sense that there is less fatigue and falls with darolutamide, and the adverse events tables from both the ARAMIS and ARASENS trials seem to support those concepts when the darolutamide arms are compared to the control arms.  Finally, there may be few drug-drug interactions when darolutamide is used.

Although the above considerations with darolutamide may seem advantageous over other androgen receptor antagonists, we lack data on direct comparisons between agents within any single trial.  There are, however, a couple of ongoing trials with direct comparisons between darolutamide and enzalutamide, focused on various quality of life issues.  The ongoing accruing clinical trials below can be broadly grouped into 2 categories.  The first is focused on quality of life considerations, ranging from erectile function, effects on testosterone, functional status, and cognitive function.  The other category is evaluation of darolutamide for other disease states, where there are no regulatory approvals, mostly studying earlier initiation of darolutamide in the neoadjuvant, adjuvant, or oligometastatic disease states; there are also some unique trials where darolutamide is being studied in the later disease state of metastatic castration-resistant prostate cancer.  Please see below for details of some select ongoing relevant trials.

Select Highlighted Trials Evaluating Darolutamide in Prostate Cancer:

With a focus on Quality of Life

• INTREPId – INTermediate risk erection preservation Trial (NCT04025372)
• ARAMON – Learning darolutamide vs. enzalutamide effects on testosterone in non-castrate men (NCT05526248)
• PEACE6-Vulnerable – ADT +/- darolutamide in de novo metastatic prostate cancer in patients with vulnerable functional ability (NCT04916613)
• ARACOG - Effect on cognitive function in patients treated with darolutamide or enzalutamide (NCT04335682)
• ExBAT Trial – Extreme bipolar androgen therapy with darolutamide and testosterone cypionate in patients with metastatic castration-resistant prostate cancer (NCT04558866)

With a focus on Other Disease States

• SChLAP/IDC - Darolutamide with degarelix and radiation in intermediate risk prostate cancer (NCT04176081)
• DARIUS - Randomized phase II trial of short term darolutamide with radiation for intermediate unfavorable risk localized prostate cancer (NCT05346848)
• Treatment deintensification for low gene risk score and intensification (with darolutamide) for higher gene risk score unfavorable intermediate risk prostate cancer (NCT05050084)
• Darolutamide with ADT in high-risk/very high-risk localized prostate cancer (NCT05249712)
• DASL-HiCaP - Darolutamide with standard therapy for very high-risk localized prostate cancer (NCT04136353)
• ALADDIN - Darolutamide with ADT and radiation in newly diagnosed pelvic lymph node positive prostate cancer (NCT05116475)
• DECREASE - Darolutamide and consolidation radiotherapy in advanced prostate cancer detected by PSMA PET (NCT04319783)
• ERADICATE Study – Darolutamide with ADT after radical prostatectomy for high-risk prostate cancer (NCT04484818)
• DART - Stereotactic body radiotherapy +/- darolutamide for oligorecurrent prostate cancer (NCT04641078)
• PCS X - Darolutamide and SBRT for oligoprogressive castration-resistant prostate cancer (NCT04070209)

References

1. Fizazi K, et al. Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med 2019; 380:1235-46.
2. Smith MR, et al. Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. N Engl J Med 2018; 378:1408-18.
3. Hussain M, et al. Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med 2018; 378:2465-74.
4. Sweeney C, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N Engl J Med 2015; 373:737-46.
5. James ND, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. N Engl J Med 2016; 387:1163-77.
6. Fizazi K, et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med 2017; 377:352-60.
7. James ND, et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N Engl J Med 2017; 377:338-51.
8. Chi KN. et al. Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med 2019; 381:13-24.
9. Armstrong A, et al. Improved Survival With Enzalutamide in Patients With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol 2022; 40:1616-22.
10. Davis IA, et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. N Engl J Med 2019; 381:121-31.
11. Fizazi K, et al. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design. Lancet 2022; 399:1695-1707.
12. Smith MR et al. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. N Engl J Med 2022; 386:1132-42.
13. FDA approves darolutamide tablets for metastatic hormone-sensitive prostate cancer. FDA.gov.
14. Moilanen AM, et al. Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies. Sci Rep 2015; 5:12007.