Darolutamide: Approved For Non-Metastatic Castration-Resistant Prostate Cancer

Published in Everyday Urology - Oncology Insights: Volume 4, Issue 3

Published Date: September 2019

Androgen deprivation therapy (ADT) is the longstanding initial treatment for advanced hormone-sensitive prostate adenocarcinoma. Nonetheless, patients who are initiated on ADT will invariably progress by developing prostate cancer cellular clonal populations, which creates a phenotype of more castration-resistant disease with more aggressive biology.1

Darolutamide (ODM-201; Nubeqa®) is an androgen receptor (AR) antagonist with high affinity for both wild-type AR and AR variants that have been associated with resistance to apalutamide (Erleada®) and enzalutamide (Xtandi®) in preclinical studies.2 In the pivotal phase 3 ARAMIS trial (Efficacy and Safety Study of Darolutamide (ODM-201) in Men With High-Risk Nonmetastatic Castration-Resistant Prostate Cancer), the addition of darolutamide to ADT significantly improved metastasis-free survival (MFS) in men with non-metastatic castration-resistant prostate cancer (nmCRPC) and rapid prostate-specific antigen (PSA) doubling times.3 Darolutamide also met its secondary and exploratory endpoints and demonstrated marked overall tolerability, especially given some of the more anticipated adverse events of interest for the novel androgen receptor antagonists. In July 2019, the U.S. Food and Drug Administration (FDA) approved darolutamide for the treatment of high-risk nmCRPC. In this article, I review the evolving nmCRPC treatment landscape, preclinical and clinical data on darolutamide, and ongoing considerations for treating patients with nmCRPC.

An Evolving Standard of Care

Non-metastatic CRPC affects approximately 110,000 men in the United States and is thought to be the preceding diagnosis for upwards of 70% of men with metastatic castration-resistant disease.4 Also described as M0 CRPC, nmCRPC may have a variable prognosis: A short (<10-month) PSA doubling time signifies a more imminent risk for the development of radiographically confirmed metastases as detected by conventional imaging (Tc bone scan and CT scan), which is an important stage of biologic progression with an approximately 70% rate of prostate cancer-specific mortality within 5 years.5-7 While researchers and clinicians long sought to extend MFS with the use of bone-targeted agents, immunotherapies, and other targeted molecules, these efforts and trials yielded unsuccessful results, and thus, until 2018, nmCRPC patients were managed by clinical observation or surveillance.8-10

Fortunately, preclinical and early-phase trials have provided important insights regarding the biologic progression of prostate cancer, which has augmented our therapeutic armamentarium. It is now known that the AR axis continues to drive prostate cancer progression after PSA relapse, suggesting that next-generation AR pathway inhibition might postpone the development of metastatic disease. In the pivotal randomized, double-blind, phase III SPARTAN and PROSPER studies, adding apalutamide or enzalutamide to ADT prolonged MFS by a median of approximately two years compared with placebo in patients with nmCRPC who also had rapid (<10-month) PSA doubling times.11,12 Both apalutamide and enzalutamide also achieved all of their prespecified secondary endpoints in their respective studies. The ensuing FDA approvals were the first in nmCRPC and the first based on a statistically and clinically meaningful improvement in MFS.11-14 Because of their clinical importance, time-to-event endpoints such as MFS have been recommended for use in clinical trials by the Prostate Cancer Clinical Trials Working Group since 2008.15

The benefits of apalutamide and enzalutamide were found to be durable with longer follow-up of patients enrolled in SPARTAN and PROSPER.16-19 However, both drugs were also associated with an increase in certain adverse events of clinical relevance for AR antagonist therapy, including fatigue, cognitive impairment, seizures, falls, fractures, and hypertension.11,12,20 This has clinical implications because patients with advanced prostate cancer often have comorbidities and are often at increased risk of frailty or dementia.21 There is a need for effective treatments for highrisk nmCRPC that either avoid or mitigate the adverse events of interest associated with AR antagonist therapy.

Overview of Darolutamide

Darolutamide is a nonsteroidal oral 1:1 mixture of two pharmacologically active diastereomers, ORM-16497 and ORM-16555, which interconvert via their major metabolite, ODM-1534.22 Like enzalutamide and apalutamide, darolutamide binds the AR, which prevents its nuclear translocation and subsequent regulation of androgen-responsive genes.23,24 However, darolutamide has a distinct chemical structure that does not resemble the molecular structures of either enzalutamide nor apalutamide. In preclinical studies, it demonstrated robust activity against both wild-type AR and AR mutations, such as AR F876L, which may be associated with enzalutamide and apalutamide resistance, and W741L and T877A, which are associated with bicalutamide and hydroxyflutamide resistance. 23,25,26

Importantly, and presumably due to its molecular polarity, darolutamide has demonstrated negligible blood-brain barrier penetration and thus a low binding affinity for γ-aminobutyric acid type A receptors (GABA AR).23,27 In an in vivo murine study, brain concentrations of carbon-14-radiolabeled darolutamide approached the lower limit of quantification and were approximately 26-fold and 46-fold lower than the respective brain concentrations of 14-C-apalutamide and 14-C-enzalutamide.27

Although drug-drug interactions can occur with darolutamide, these are less of a concern than for enzalutamide or apalutamide, both of which are potent CYP3A4 inducers. Darolutamide has demonstrated weak or no effects on CYP3A4, P-glycoprotein, or other CYP enzymes in in vitro studies and a small in vivo study of healthy men.28 However, the FDA label for darolutamide cautions against its concomitant use with P-gp and strong or moderate CYP3A4 inducers.29

The Phase 2 ARADES Trial

The phase 1/2 ARADES trial evaluated the safety, pharmacokinetics, and antitumor activity of darolutamide in 134 patients with progressive metastatic CRPC.30 During the phase I dose-escalation component of the trial, 24 patients received a daily dose of 200 to 1800 mg darolutamide while remaining on ADT.30 After a median of 25 months of darolutamide therapy, 17 of 21 evaluable patients experienced a PSA response (at least a 50% decrease in PSA from baseline); PSA responses occurred across all dose cohorts. There were no dose-limiting toxicities and no grade 3-4 adverse events that were considered treatment-related.

In the phase II dose-expansion component, an additional 110 patients were randomly assigned to receive 200, 400, or 1400 mg oral darolutamide daily.30 After a median of 11 months of treatment, the primary endpoint, PSA response at week 12, was met for 29% of patients in the 200-mg dose cohort, 33% of patients in the 400-mg cohort, and 33% of patients in the 1400-mg cohort. Patients who had not previously received chemotherapy or a CYP17 inhibitor had the highest rates of PSA response (69% in the 400-mg cohort and 86% in the 1400-mg cohort). Median time to PSA progression (based on Prostate Cancer Working Group 2 criteria) was 17 months among chemotherapy and CYP inhibitor-naive patients, versus 5 months among patients who had previously received chemotherapy and 4 months among patients who had previously received CYP17 inhibitor therapy.

The safety population in the ARADES trial included 124 patients.30 The most common treatment-emergent adverse events were fatigue or asthenia (15 patients, or 12%), hot flashes (5%), decreased appetite (4%), diarrhea (2%), and headache (2%). The only grade 3 event that was considered to be treatment-emergent was fatigue, which occurred in one patient (<1%). Fatigue was also the only treatment-emergent adverse event leading to treatment discontinuation. There was no grade 4 or grade 5 treatment-emergent events. No seizures were reported.30

The Phase 3 ARAMIS Trial

The multicenter, randomized, double-blind, phase III ARAMIS trial (NCT02200614) enrolled 1,509 patients with nmCRPC based on conventional imaging (computerized tomography [CT] and bone scans) who had rapid PSA doubling times (<10 months). Patients continued on ADT while initiating either oral darolutamide (300 mg twice daily) or placebo.3

After a median follow-up of 17.9 months, median MFS was 40.4 months in the darolutamide arm and 18.4 months in the placebo arm, demonstrating that darolutamide was associated with a 59% decrease in the risk of metastasis or all-cause mortality (hazard ratio [HR], 0.41; 95% CI, 0.34 to 0.50; P<.001).3 Darolutamide also was associated with a significant MFS benefit compared to placebo in subgroups stratified by demographics, baseline PSA level, PSA doubling time (<6 months or >6 months), use of osteoclast-targeted therapy, Gleason score, Eastern Cooperative Oncology Group (ECOG) score, number of prior hormonal therapies, and the presence or absence of pathologic regional lymph nodes.

Darolutamide also met its prespecified secondary endpoints in ARAMIS.3,11,12 Median times to pain progression, as measured by the Brief Pain Inventory Short Form, were 40.3 months with darolutamide versus 25.4 months with placebo (HR, 0.65; 95% CI, 0.53 to 0.79; P<.001).3 Median time to initiation of first cytotoxic chemotherapy was not reached with darolutamide and 28.2 months with placebo (HR, 0.43; 95% CI, 0.31 to 0.60; P<.001). Darolutamide also was associated with a 57% reduction in the risk of developing a symptomatic skeletal event (HR, 0.43; 95% CI, 0.22 to 0.84; P=.011). Patients in the darolutamide and placebo arms experienced comparable quality-of-life scores overall, and the darolutamide arm showed a significant improvement in time to urinary symptom worsening on the EORTC-QLQ-PR25, a validated, prostate cancer-specific quality-of-life instrument.3 Median time to urinary symptom worsening was 25.8 months with darolutamide versus 14.8 months with placebo (HR, 0.64; 95% CI, 0.54–0.76; P<0.01).

In exploratory analyses, darolutamide also was associated with clinically and statistically significant improvements in progression-free survival (median durations, 36.8 vs. 14.8 months; HR, 0.38; 95% CI, 0.32 to 0.45; P<.001) and time to PSA progression (medians, 33.2 vs, 7.3 months; HR, 0.13, 95% CI, 0.11 to 0.16; P<.001).

Prostate-specific antigen levels decreased from baseline by 50% or more in 84% of patients receiving darolutamide compared with 8% of those receiving placebo. Median time to first prostate cancer-related invasive procedure and median time to initiation of subsequent anti-neoplastic therapy were not reached in either arm, although both hazard ratios favored darolutamide over placebo (0.39 and 0.33, respectively; both P<.001).3

The safety population of ARAMIS included 1,508 patients.3 As in the phase 1/2 ARADES trial, the majority of treatment-emergent adverse events were grade 1 or 2 (54.6% in the darolutamide arm and 54.2% in the placebo arm), and the most common adverse event was fatigue, which affected similar proportions of patients in each arm (all-grade fatigue, 12.1% with darolutamide and 8.7% with placebo; grade 3-4 fatigue, 0.4% and 0.9% of patients, respectively). Rates of serious adverse events also were similar between arms (24.8% and 20%, respectively), as were grade 5 events (3.9% and 3.2%) and adverse events of special interest, including fractures, falls, seizures, rash, weight loss, dizziness, cognitive or memory impairment, changes in mental status, coronary artery disorders, and heart failure.

As in the ARADES trial, patient-reported quality of life was similar between arms. Compared with placebo, darolutamide was associated with relatively small but statistically significant improvements on the Brief Pain Inventory Short-Form, the Functional Assessment of Cancer Therapy-Prostate tool, and the EORTC-QLQ-PR25 urinary symptoms subscale. Based on the results of the phase 1-3 trials of darolutamide, the FDA approved darolutamide for the treatment of nmCRPC at a dose of 600 mg (two 300-mg tablets), administered orally twice daily.29 It is worth noting that in the open-label phase 1 ARAFOR trial, the bioavailability of darolutamide (600 mg) was two times higher in the fed versus the fasted state.34

Considerations for Clinical Practice

Whom to treat?

The magnitude of effect in PROSPER, SPARTAN, and ARAMIS supports the use of early, potent next-generation androgen receptor inhibition in appropriately selected patients with nmCRPC.14 The demonstrated efficacy of apalutamide, enzalutamide, and darolutamide is especially noteworthy when we consider that patients in the placebo-ADT arms received additional treatment at the onset of radiographically confirmed metastatic disease.3,11,12

The FDA-labeled indications for these drugs do not specify PSA doubling time, which could lead to the perception that all patients with nmCRPC should receive additional treatment as soon as they develop castration resistance. Instead, treatment should be limited to patients with high-risk nmCRPC per the registrational trial inclusion criteria. Most patients in these trials actually had much shorter doubling times than the enrollment criterion of 10 months; median PSA doubling times were approximately 3.7 months in PROSPER and approximately 4.5 months in SPARTAN and ARAMIS.3,11,12 In addition, some of these trials permitted the enrollment of patients with N1 disease (malignant pelvic lymph nodes measuring less than 1.5 or 2 cm in the short axis).3,11

Although next-generation imaging was not utilized in any of the three trials, it is likely that many patients would have had positive PSMA PET/CT scans.31 That said, we have a paucity of data on the efficacy of second-generation anti-androgen therapy for mCRPC when decision-making is based solely on next-generation imaging (NGI) findings. Assuredly, primum non nocere (above all, do no harm), and this includes avoiding suboptimal therapies, inappropriate therapies, drug interactions, and unnecessary adverse events associated with individual comorbidities. In lieu of reflexively recommending and prescribing additional therapies when patients with prostate cancer develop castration-resistant disease, we must invoke shared decision-making with patients and caregivers and carefully balance their priorities (risk-benefit assessment for clinical improvement versus adverse reactions), overall health status, and the financial accessibility of therapy against the likelihood of clinically significant disease progression.

Which drug?

The rapidity of drug development and regulatory approvals in advanced prostate cancer has greatly expanded our treatment armamentarium, but we have a dearth of comparative head-to-head trials. While PROSPER, SPARTAN, and ARAMIS had very similar study designs and patient risk characteristics, we can only compare them based on their published and publicly presented information.

Median MFS times were very similar in all three studies (40.4 months with darolutamide, 36.6 months with enzalutamide, and 40.4 months with apalutamide, versus 18.4 months, 14.7 months, and 16.2 months in the respective placebo arms). Overall survival data are pending, and we anticipate a readout soon, which will hopefully augment the MFS composite endpoint. All three drugs also achieved their secondary and exploratory endpoints in these pivotal trials.

There may be differences when we assess safety and tolerability. Darolutamide appears to have demonstrated less adverse events with regard to the spectrum of neurocognition. In contrast, apalutamide and enzalutamide were associated with an increased risk of fatigue/asthenia, falls, fractures, and seizures relative to placebo.3,11,12,14

In a meta-analysis of four phase 3 trials comparing enzalutamide with placebo in men with non-metastatic or metastatic CRPC (PROSPER, PREVAIL, AFFIRM, and 9785-CL-0232), enzalutamide was associated with a two to three-fold increase in the risk of falls and fractures.32 In SPARTAN, all-grade fractures occurred in 11.7% of patients who received apalutamide and 6.5% of patients who received placebo, while rates of grade 3-4 fractures were 2.7% and 0.8%, respectively.11 Additionally, the only two events of seizure occurred in the apalutamide arm. Darolutamide has not been associated with a similar increase in risk of falls or fractures.3,30 Likewise, rates of fatigue were 33% in the PROSPER trial, 30.4% in the SPARTAN trial, and 12.1% in the ARAMIS trial. Different reporting methodologies may account for these differences and, as has been previously stated, there is a need for direct prospective head-to-head trials to assess safety and tolerability in a fair and balanced manner.

An increased risk of treatment-emergent cardiovascular events has been observed with enzalutamide and apalutamide. In the PROSPER trial, rates of major adverse cardiovascular events (MACE) were 5% with enzalutamide and 3% with placebo.12 In the previously described meta-analysis of four phase 3 studies, rates of enzalutamide-emergent ischemic heart disease and cardiac death were 2.6% and 0.4%, respectively, two to four times higher than in the placebo group.32 In the SPARTAN trial, apalutamide was associated with an increase in all-grade and grade 3-4 hypertension (24.8% and 14.3%, respectively, versus 19.8% and 11.8% with placebo), and rates of death from myocardial infarction, cardiorespiratory arrest, or cerebral hemorrhage were in 0.49% in the apalutamide arm versus 0.25% in the placebo arm.3

In ARAMIS, darolutamide was associated with slightly higher rates of all-grade and grade 3-4 hypertension compared with placebo (6.6% vs. 5.2% and 3.1% vs. 2.2%, respectively). This was also the case for coronary-artery disorder (3.1% with darolutamide vs. 2.5% with placebo) and heart failure (1.9% vs. 0.9%, respectively). All the nmCRPC trials excluded patients with significant cardiovascular disease, which may suggest that the risk of treatment-emergent cardiovascular events may be higher in community practice prescribing. Hence, it is essential to screen and measure cardiovascular risk factors (routine blood pressure at baseline and follow-up visits, assessment of relevant comorbidities, such as hyperlipidemia) and to educate patients regarding the role of exercise and diet in improving both cardiometabolic and efficacy outcomes during prostate cancer treatment. In addition, polypharmacy and a review of potential drug-drug interactions are important considerations for optimizing our patients’ cancer care.

Assessing treatment response

It appears prudent to have patients return two weeks after initiating a novel AR antagonist for nmCRPC to assess blood pressure, drug tolerance, and any changes in symptoms. When assessing treatment response, it is important to recognize that PSA decline is only one indicator of tumor AR signaling activity. The molecular biology of prostatic adenocarcinoma evolves in response to treatment, and a decline in PSA does not necessarily rule out disease progression.6 Identifying additional histologic, molecular, and genomic biomarkers of prognosis and treatment response is an area of active study that will hopefully yield additional tools to assess and even predict treatment response in nmCRPC. For example, apalutamide has been found to be more effective in patients with nmCRPC who have higher scores on DECIPHER, a commercially available genomic assay, as well as in patients with luminal (rather than a basal) tumor subtypes.33


In July 2019, darolutamide became the third drug to receive FDA approval for the treatment of nmCRPC. The efficacy of the three approved therapies appears very similar, but the published literature suggests differences in adverse events of interest associated with AR antagonists, including rates of falls, fractures, fatigue, cognitive impairment, and hypertension.3,11,12 These findings should be confirmed by longer-term post-market safety registries and prospective comparator trials. Careful monitoring of nmCRPC patients is essential to assess safety, treatment response and the detection of eventual progression to mCRPC disease.

Written by: Neal Shore, MD, FACS is director for the Carolina Urologic Research Center and is the managing partner for Atlantic Urology Clinics in Myrtle Beach, South Carolina. Dr. Shore serves on the boards of the Society of Urologic Oncology Board of Directors, the Society Urologic Oncology Clinical Trials Consortium, the Large Urology Group Practice Association, NCI GU Science Steering Committee and the Urology Times.


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15. Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008;26:1148-1159.

16. Small EJ, Saad F, Chowdhury S, et al. Updated analysis of progression-free survival with first subsequent therapy (PFS2) and safety in the SPARTAN study of apalutamide (APA) in patients (pts) with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC). Paper presented at: American Society for Clinical Oncology Genitourinary Cancers Symposium; February 14, 2019; San Francisco, CA. https://meetinglibrary.asco.org/record/170216/abstract Accessed February 17, 2019.

17. Saad F, Morlock R, Ivanescu C, et al. Association between urinary, bowel, and hormonal treatment-related symptoms and clinical outcomes in nonmetastatic castration-resistant prostate cancer (nmCRPC): PROSPER study. Poster presented at: American Society for Clinical Oncology Genitourinary Cancers Symposium; February 14, 2019; San Francisco, CA. https://meetinglibrary. asco.org/record/169844/abstract Accessed February 17, 2019.

18. Tombal BF, Saad F, Penson D, et al. Patient-reported outcomes following enzalutamide or placebo in men with non-metastatic, castration-resistant prostate cancer (PROSPER): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2019 Feb 12. doi: 10.1016/S1470- 2045(18)30898-2 [Epub ahead of print]

19. De Giorgi U, Efsathiou E, Berry WR, et al. A phase III, randomized, double-blind, placebo-controlled study of enzalutamide in men with nonmetastatic castration-resistant prostate cancer: Post-hoc analysis of PROSPER by prior therapy. Poster presented at: American Society for Clinical Oncology Genitourinary Cancers Symposium; February 14, 2019; San Francisco, CA. https://meetinglibrary.asco.org/record/170134/abstract Accessed February 18, 2019.

20. Iacovelli R, Verri E, Cossu rocca M, et al. The incidence and relative risk of cardiovascular toxicity in patients treated with new hormonal agents for castration-resistant prostate cancer. Eur J Cancer. 2015 Jul 10;51(14):1970-1977.

21. Whitney CA, Howard LE, Freedland SJ, et al. Impact of age, comorbidity, and PSA doubling time on long-term competing risks for mortality among men with non-metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis. 2018 Oct 2. [Epub ahead of print]

22. Shore, ND. Darolutamide (ODM-201) for the treatment of prostate cancer. Expert Opinion on Pharmacotherapy, 18:9, 945-952.

23. Smith MR. Progress in nonmetastatic prostate cancer. N Engl J Med. 2018 Jun 28;378(26):2531-2532.Moilanen AM, Riikonen R, Oksala R, 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.

24. Nguyen MM, Dincer Z, Wade JR, et al. Cytoplasmic localization of the androgen receptor is independent of calreticulin. Mol Cell Endocrinol. 2009;302(1):65-72.

25. Fizazi K, Albiges L, Loriot Y, Massard C. ODM-201: a new-generation androgen receptor inhibitor in castration-resistant prostate cancer. Expert Rev Anticancer Ther. 2015;15(9):1007-1017.

26. Fizazi K, Shore ND, Tammela T, et al. Impact of darolutamide (DARO) on pain and quality of life (QoL) in patients (Pts) with nonmetastatic castrate-resistant prostate cancer (nmCRPC). J Clin Oncol 2019;37(no. 15_suppl):5000-5000.

27. Zurth C, Sandmann S, Trummel D, Seidel D, Gieschen H. Blood-brain barrier penetration of [14C] darolutamide compared with [14C]enzalutamide in rats using whole body autoradiography. J Clin Oncol 2018;36 (6S_suppl):345-345.

28. Zurth C, Graudenz K, Denner K, et al. Drug-drug interaction (DDI) of darolutamide with cytochrome P450 (CYP) and P-glycoprotein (P-gp) substrates: Results from clinical and in vitro studies. J Clin Oncol. 2019;37(no. 7_suppl):297-297.

29. U.S. Food and Drug Administration. Nubeqa® (darolutamide): Highlights of prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212099Orig1s000lbl.pdf Published July 2019. Accessed August 24, 2019.

30. izazi K, Massard C, Bono P, et al. Activity and safety of ODM-201 in patients with progressive metastatic castration-resistant prostate cancer (ARADES): an open-label phase 1 dose-escalation and randomised phase 2 dose expansion trial. Lancet Oncol. 2014;15(9):975-985.

31. Hadaschik BA, Weber M, Iravani A, et al. Prostate-specific membrane antigen positron-emission tomography (PSMA-PET) in high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC) SPARTAN-like patients (pts) negative by conventional imaging. Eur Urol Suppl. 2019;18(1):e698-e699.

32. Tombal BF, Armstrong AJ, Barrus JK, et al. Adverse events of special interest assessed by review of safety data in enzalutamide castration-resistant prostate cancer (CRPC) trials. Poster presented at: American Society for Clinical Oncology Genitourinary Cancers Symposium; February 14, 2019; San Francisco, CA. https://meetinglibrary.asco.org/record/170029/abstract Accessed February 18, 2019.

34. Feng FY, Thomas S, Gormley M, et al. Identifying molecular determinants of response to apalutamide (APA) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) in the SPARTAN trial. Poster presented at: American Society for Clinical Oncology Genitourinary Cancers Symposium; February 14, 2019; San Francisco, CA. https://meetinglibrary.asco.org/record/170087/abstract Accessed February 17, 2019.

34. Massard C, Penttinen HM, Vjaters E, et al. Pharmacokinetics, anti-tumor activity, and safety of ODM-201 in patients with chemotherapy-naive metastatic castration-resistant prostate cancer: an open- label phase 1 study. Eur Urol. 2016;69:834-840.