Non-metastatic castration-resistant prostate cancer is a heterogeneous disease: some patients experience gradual disease progression, while others have aggressive prostate-specific antigen (PSA) kinetics characterized by higher absolute PSA levels and rapid PSA doubling times, which are independent risk factors for metastatic progression and cancer-related death.2-5 Until recently, well-designed studies had not identified therapies for nmCRPC that delayed progression and prolonged survival, and patients were managed by observation, with empiric medical therapeutics, or awaiting additional treatment upon progression in order to confirm imaging positive metastatic CRPC (mCRPC) disease.
Men with nmCRPC are invariably asymptomatic, notwithstanding sequelae of testosterone suppression, and thus remain active for both work and lifestyle activities. Consequently, nmCRPC patients can benefit from treatment that will delay disease progression and also prolong survival while allowing for a favorable safety and tolerability profile consistent with maintaining the quality of life.5
The U.S. Food and Drug Administration (FDA) has recently approved three next-generation oral androgen receptor (AR) pathway inhibitors, darolutamide, enzalutamide, and apalutamide, for the treatment of nmCRPC based on the results of the pivotal randomized, placebo-controlled, double-blinded ARAMIS, PROSPER, and SPARTAN trials, respectively.6-8 All three of these drugs inhibit the androgen receptor (AR) pathway by binding the AR to prevent its regulation of androgen-responsive genes.9,10
Of note, darolutamide is structurally distinct from enzalutamide and apalutamide, consisting of two pharmacologically active diastereomers that target wild-type AR and several genetic mutations associated with resistance to next-generation AR therapies.10 Of additional importance, darolutamide also has been found to minimally penetrate the blood-brain barrier, which may lessen neurocognitive side effects. Darolutamide has also demonstrated a low potential for drug-drug interactions with medications that are commonly used in the nmCRPC patient population, for example, including statins, anticoagulants, antidepressants, and calcium channel blockers.8,10-13
In the primary analysis of the ARAMIS trial, darolutamide significantly improved metastasis-free survival and key secondary efficacy endpoints; darolutamide exhibited a favorable safety profile compared to placebo. However, overall survival data were immature at the initial data cutoff and at the time of FDA approval. At the American Society of Clinical Oncologists 2020 Virtual Annual Meeting, Karim Fizazi, MD, PhD, and co-investigators reported the final overall survival analysis for the ARAMIS trial as well as updated results for key secondary endpoints, metastasis-free survival and safety.14 The findings support the use of darolutamide treatment for nmCRPC in appropriately selected patients. Herein, I review important findings from the ARAMIS trial and discuss their implications for current clinical practice and future clinical trials.
Trial Design and Primary Analysis
The international, double-blind, placebo-controlled, phase III ARAMIS trial enrolled 1,509 men diagnosed with nmCRPC whose baseline PSA was at least 2 ng per milliliter and whose PSA doubling time was less than or equal to 10 months.8 Patients were randomly assigned on a 2:1 basis to receive 600 mg darolutamide twice daily (totaling 1200 mg per day) or placebo. All patients received continued ADT. The primary study endpoint was metastasis-free survival, defined as the time from randomization to the first confirmed evidence of distant metastasis on imaging, or death from any cause, whichever occurred first.
Secondary endpoints included overall survival, time to progression of pain (assessed by the Brief Pain Inventory Short- Form questionnaire), time to first cytotoxic chemotherapy, and time to first symptomatic skeletal event.8 Efficacy was evaluated for the intention-to-treat population, which consisted of all patients who were randomized. Safety was evaluated for all patients who received at least one dose of study drug. Health-related quality-of-life was assessed with the Functional Assessment of Cancer Therapy-Prostate (FACT-P), the generic EuroQol Group 5-dimension 3-level (EQ-5D-3L), and the European Organisation for Research and Treatment of Cancer quality of life questionnaire urinary symptoms subscale (EORTC-QLQ-PR25).
The results of the primary efficacy analysis of the ARAMIS trial were reported in 2019.8 At the time of data cutoff, patients had been followed for a median of 17.9 months. The median duration of metastasis-free survival was 40.4 months for darolutamide added to ADT versus 18.4 months for placebo added to ADT; darolutamide was associated with a 59% reduction in the risk of metastasis or death (hazard ratio, 0.41; 95% confidence interval, 0.34 to 0.50; P < .0001). Darolutamide demonstrated similar effects on metastasis-free survival in prespecified subgroups, such as patients whose PSA doubling time was less than or equal to 6 months or greater than 6 months (most patients in the ARAMIS trial had a PSA doubling time less than or equal to 6 months).
Darolutamide also met prespecified secondary efficacy endpoints in the ARAMIS trial, including time to progression of pain (median 40.3 months for darolutamide vs. 25.4 months for placebo; HR, 0.65; 95% CI, 0.53 to 0.79; P < .001), time to administration of cytotoxic chemotherapy (median not reached vs. 38.2 months; HR, 0.43; 95% CI, 0.31 to 0.60; P < .001), and time to first symptomatic skeletal event (median not reached in either group; HR, 0.43; 95% CI, 0.22 to 0.84; P = .01). Darolutamide also was associated with statistically significant improvements in time-to-event exploratory analyses, including progression-free survival, time to PSA progression, time to first invasive procedure related to prostate cancer, and time to initiation of subsequent anticancer therapy.
Compared with placebo, darolutamide demonstrated minimal or no impact on the following adverse events heretofore observed with next-generation AR inhibitors, including falls and fractures, hypertension, seizures, and cognitive impairment disorders.8 Combining darolutamide to ADT did not decrease patient-reported quality of life compared with placebo.
Among patients who developed distant metastases (mCRPC), anatomical patterns of metastases were similar between arms. Bone-only disease was present in 46% of darolutamide recipients and 39% of placebo recipients, while node-only metastases were identified in 32% and 40% of patients, lymph node and bone metastases were observed in 13% and 14% of patients, and distant metastases at other sites occurred in 9% and 7% of patients, respectively.15 A small proportion of patients in the ARAMIS trial did have baseline metastases identified by independent central radiographic review (this included 50 patients in the darolutamide arm and 39 patients in the placebo arm).16 These patients were included in all analyses. Notably, sensitivity analyses demonstrated that the treatment effect of darolutamide on metastasis-free survival was consistent regardless of whether patients had metastases at baseline.
Overall survival was a secondary endpoint in the ARAMIS trial for which data were immature at the time of the primary analysis. At the prespecified interim analysis, the median duration of survival was not reached in either study arm. However, darolutamide showed a statistical trend toward improving overall survival compared with placebo (HR for death, 0.71; 95% CI, 0.50 to 0.99; P = .045).
Final Efficacy and Safety Findings
The results of the final overall survival analysis of the ARAMIS trial were reported this year at ASCO 202014,17 and are forthcoming in the New England Journal of Medicine. In the intention-to-treat population, darolutamide was associated with significantly improved overall survival, met all other secondary endpoints, and continued to demonstrate a favorable safety profile.
At data cutoff in November 2019, patients had been followed for a median of 29.1 months. In the Kaplan-Meier analysis of overall survival, adding darolutamide to ADT was associated with a statistically significant 31% reduction in the risk of death compared to placebo plus ADT (HR, 0.69; 95% CI, 0.53 to 0.88; P = .003).14 Three-year overall survival was 83% (95% CI, 80% to 86%) for darolutamide and 77% (95% CI, 72% to 81%) for placebo. This overall survival benefit occurred even though 56% (309 of 554) patients in the placebo group received subsequent life-prolonging therapies (including darolutamide, docetaxel, abiraterone, enzalutamide, sipuleucel-T, and cabazitaxel) after progressing to overt metastatic disease.
Darolutamide also was associated with improved overall survival in pre-specified subgroups of patients stratified by PSA doubling time (less than or equal to 6 months or greater than 6 months), the baseline presence or absence of nodal disease, Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1), and geographic region.14 Although confidence intervals crossed 1.0 in some smaller subgroups, the trend favoring improved survival with darolutamide was consistent.
In the updated analyses of other secondary endpoints, adding darolutamide to ADT significantly delayed time to pain progression (median, 40.3 months vs. 25.4 months with placebo plus ADT; HR, 0.65; 95% CI, 0.53 to 0.79; P < .001), time to first cytotoxic chemotherapy (HR, 0.58, 95% CI, 0.44 to 0.76; P < .001), and time to first symptomatic skeletal event (HR, 0.48, 95% CI, 0.29 to 0.82; P = .005).14 All exploratory analyses also favored darolutamide, including time to first prostate cancer-related procedure (HR, 0.42; 95% CI, 0.28 to 0.62; P < .001) and time to initiation of subsequent antineoplastic therapy (HR, 0.36; 95% CI, 0.27 to 0.48; P < .001).
The final safety analysis of the ARAMIS trial represented an additional 11 months of median follow-up time as compared with the primary analysis.8,14 No new safety signals were identified with longer-term follow-up. Darolutamide continued to demonstrate a favorable safety profile that resembled the findings of the primary analysis. During the double-blind study period, rates of adverse events of any grade were 85.7% for darolutamide and 79.2% for placebo.17 Grade 3-4 (moderate to severe) adverse events were present in 26.3% and 21.7% of patients, respectively. Serious adverse events affected 26.1% and 21.8% of patients, and fatal (grade 5) adverse events affected 4% and 3.4% of patients. Adverse events leading to treatment discontinuation affected nearly identical proportions of patients in each arm (8.9% and 8.7%). After unblinding, adverse events among patients who crossed over from placebo to darolutamide resembled those among patients randomized to darolutamide.
Fatigue was the only adverse event documented in more than 10% of patients during the double-blind study period, affecting 13.2% of patients who received darolutamide and 8.3% of patients who received placebo. However, after controlling for differences in duration of treatment exposure, the incidence of fatigue during the double-blind study period was comparable between arms (8.3 vs. 7.4 events per 100 person-years of exposure to darolutamide or placebo, respectively). Rates of grade 3-4 fatigue were low (less than 1%) and similar between arms. The incidence of rash was 3.1% for darolutamide versus 1.1% for placebo. Rates of other adverse events of special interest for AR inhibitor therapy, including mental impairment disorders, fractures, falls, hypertension, seizures, rash, depressed mood disorders, and hot flushes, were both low as well as similar between arms.7
Cardiac arrhythmias were more frequent with darolutamide (7.3%) than placebo (4.3%),14 but arrhythmias were more frequent at baseline in the darolutamide arm, as has been previously reported.8 Darolutamide was associated with a less than 2% increase in the incidence of coronary artery disorders and heart failure.
Darolutamide was approved for nmCRPC patients on July 30, 2019; hence, studies of its safety and tolerability in real-world nmCRPC populations are still limited. I have found that most patients tolerate darolutamide very well, with minimal reports of adverse events, including those that are commonly associated with other AR inhibitor therapies.
For prostate cancer patients receiving ADT, the onset of biochemical (PSA) relapse signifies disease-biologic progression consistent with the development of ADT-resistant tumor clones which now predisposes patients for an increased risk for progression to CRPC disease. In the ARAMIS final analysis, adding darolutamide to ADT was associated with a statistically significant 31% reduction in the risk of death among men with high-risk nmCRPC after a median of 29.1 months of follow-up.14 Notably, this treatment effect was observed even though most patients in the placebo arm subsequently received life-prolonging therapy. This clinically beneficial outcome supports the physician-patient shared decision making discussion of AR inhibition for patients with nmCRPC who are at risk for metastatic progression.
In ARAMIS, the darolutamide arm also resulted in significant improvement in all other secondary endpoints, including time to pain progression, time to cytotoxic chemotherapy, and time to first symptomatic skeletal event.14 As in the primary analysis, darolutamide significantly prolonged the primary endpoint of metastasis-free survival; the congruence of treatment benefit effects of darolutamide on metastasis-free survival and overall survival fortifies the prior supposition that metastasis-free survival is a valid surrogate endpoint for overall survival among patients with nmCRPC.6,7
Final overall survival analyses of the SPARTAN and PROSPER trials were also reported at this year’s ASCO 2020.18,19 Both apalutamide and enzalutamide were associated with statistically significant increases in median overall survival compared with placebo (apalutamide: 73.9 vs. 59.9 months, respectively; HR for death, 0.78, 95% CI, 0.64 to 0.96; P = .0161; enzalutamide: 67.0 vs. 56.3 months; HR for death, 0.73; 95% CI, 0.61 to 0.89; P = .001). The overall survival findings most recently presented at ASCO 2020 from ARAMIS, PROSPER, and SPARTAN, provide compelling evidence-based data for the use of next-generation AR inhibitor treatment rather than surveillance for men with high-risk nmCRPC.6-8
Many similarities exist among the SPARTAN, PROSPER, and ARAMIS trials. All participants had high-risk nmCRPC, defined as a baseline PSA of 2 ng per milliliter and a PSA doubling times of 10 months or less, and the primary endpoint in each trial was metastasis-free survival as assessed by CT and bone scan of the pelvis, chest, and abdomen every 16 weeks.6-8 Nodal disease was present, but limited (ARAMIS and SPARTAN permitted the enrollment of patients with malignant nodes below the aortic bifurcation measuring less than 2 cm in diameter, while the SPARTAN trial set a threshold of less than 1.5 cm).6,8,20 All patients received ADT throughout treatment. In the primary analyses, apalutamide, enzalutamide, and darolutamide each were associated with an approximately two-year increase in median metastasis-free survival compared with placebo when added to ADT.6-8 All three drugs also significantly improved key secondary efficacy endpoints.
Therapeutic safety and tolerability are vital in cancer care and also essential to optimize adherence to oral medications.21 Thus far, the primary differences among apalutamide, enzalutamide, and darolutamide appear to lie in their safety profiles as compared with the placebo comparator arm of each trial. In the SPARTAN trial, adverse events occurring at a higher (>3%) frequency with apalutamide than placebo included fatigue, rash, hypertension, weight loss, arthralgias, hypothyroidism, dizziness, falls, and fractures.6 In the PROSPER trial, enzalutamide was associated with an increased incidence of fatigue, dizziness, falls, mental impairment disorders, hot flushes, weight loss, hypertension, and major adverse cardiovascular events. In the ARAMIS trial, darolutamide demonstrated increases in adverse events, notable for fatigue and rash.
Androgen receptor inhibition can induce or exacerbate cardiovascular disease. While long-term conventional ADT is known to contribute to cardiovascular morbidity,22 there is increasing evidence that next-generation AR inhibitors may also have adverse cardiovascular effects.23 In the ARAMIS trial, cardiac arrhythmias were more frequent with darolutamide than placebo, but this was also the case at baseline, and darolutamide was not associated with an increased incidence of other adverse cardiovascular events.
The published safety profiles of apalutamide, enzalutamide, and darolutamide are important, yet ultimately require clinician real world experience with the use of these therapies for nmCRPC management. However, head-to-head studies are needed to directly compare their safety and tolerability differences. For darolutamide, such trials are planned or currently are recruiting. The phase II ARACOG trial (NCT04335682) will assess and compare specific neurocognitive outcomes in patients with non-metastatic or metastatic CRPC who are randomly assigned to receive either enzalutamide or darolutamide. Researchers will compare functional MRI scans and changes in cognitive domains during treatment and after crossover. Also, the phase II DaroAcT trial (NCT04157088) will evaluate changes in Time Up and Go (TUG) assessment and other measures of physical performance, as well as cognitive function, fatigue, and other adverse events of interest, among men with non-metastatic or metastatic CRPC randomly assigned to enzalutamide or darolutamide.24 The results of the ARACOG and DaroACT studies will facilitate a direct comparison of the safety profiles of two approved nmCRPC therapies and may also elucidate mechanisms of cognitive impairment in AR inhibition.
Additional studies of darolutamide are underway. For men with metastatic hormone-sensitive prostate cancer, the ongoing phase III ARASENS trial evaluates darolutamide or placebo added to standard ADT and docetaxel (a current standard of care). The trial has completed accrual and enrolled 1,300 subjects who were randomized 1:1 for the abovementioned regimens, with stratification at baseline for disease burden.25 ARASENS and other ongoing mCSPC studies should clarify the role of novel AR inhibitors as a component of triplet regimens for the treatment of metastatic androgen-sensitive prostate cancer.
nmCRPC patients with appropriate PSA kinetics face a significantly increased risk for progression to mCRPC and cancer-specific mortality. In the final analysis of the randomized, double-blind, placebo-controlled ARAMIS trial, adding darolutamide to ADT significantly improved overall survival, metastasis-free survival, and other key efficacy endpoints, even though most patients in the placebo arm subsequently received life-prolonging therapies. These data support early AR targeting for men with high-risk nmCRPC, and treatment selection should consider a safety profile that supports quality of life maintenance. In the ARAMIS trial, darolutamide was associated with few increases in adverse events frequently associated with next-generation AR inhibition, such as falls, seizures, hypertension, and cognitive impairment. The ARAMIS trial supports the consideration of darolutamide for appropriately selected patients with nmCRPC.
Written by: Neal Shore, MD, FACS, Editor-in-Chief, Everyday Urology - Oncology Insights, UroToday.com, Medical Director, The Carolina Urologic Research Center, Myrtle Beach, South Carolina
- Gillessen S, Attard G, Beer TM, et al. Management of Patients with Advanced Prostate Cancer: Report of the Advanced Prostate Cancer Consensus Conference 2019. Eur Urol 2020;77:508-47.
- Howard LE, Moreira DM, De Hoedt A, et al. Thresholds for PSA doubling time in men with non-metastatic castration-resistant prostate cancer. BJU Int 2017;120:E80-e6.
- Markowski MC, Chen Y, Feng Z, et al. PSA Doubling Time and Absolute PSA Predict Metastasis-free Survival in Men With Biochemically Recurrent Prostate Cancer After Radical Prostatectomy. Clin Genitourin Cancer 2019;17:470-5.e1.
- McKay R, Haider B, Duh MS, et al. Impact of symptomatic skeletal events on health-care resource utilization and quality of life among patients with castration-resistant prostate cancer and bone metastases. Prostate Cancer Prostatic Dis 2017;20:276-82.
- Mateo J, Fizazi K, Gillessen S, et al. Managing Nonmetastatic Castration-resistant Prostate Cancer. Eur Urol 2019;75:285-93.
- Smith MR, Saad F, Chowdhury S, et al. Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. N Engl J Med 2018;378:1408-18.
- Hussain M, Fizazi K, Saad F, et al. Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med 2018;378:2465-74.
- Fizazi K, Shore N, Tammela TL, et al. Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med 2019;380:1235-46.
- Nguyen MM, Dincer Z, Wade JR, et al. Cytoplasmic localization of the androgen receptor is independent of calreticulin. Mol Cell Endocrinol 2009;302:65-72.
- 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.
- Zurth C, Koskinen M, Fricke R, et al. Drug-Drug Interaction Potential of Darolutamide: In Vitro and Clinical Studies. Eur J Drug Metab Pharmacokinet 2019;44:747-59.
- Fizazi 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;15:975-85.
- Shore N, Zurth C, Fricke R, et al. Evaluation of Clinically Relevant Drug-Drug Interactions and Population Pharmacokinetics of Darolutamide in Patients with Nonmetastatic Castration-Resistant Prostate Cancer: Results of Pre-Specified and Post Hoc Analyses of the Phase III ARAMIS Trial. Target Oncol 2019;14:527-39.
- Fizazi K, Shore ND, Tammela TL, et al. Overall survival resullts of the phase III ARAMIS study of darolutamide added to androgen deprivation therapy for non-metastatic castration-resistant prostate cancer. ASCO Virtual Scientific Program 2020.
- Pang JST, Shore N, Smith MR, et al. Efficacy and safety of darolutamide in non-metastatic castration-resistant prostate cancer (nmCRPC) in the ARAMIS trial. Ann Oncol 2019;30:ix69.
- Supplement to: Fizazi, K, Shore N, Tammela T, et al. Darolutamide in Nonmetastatic Castration- Resistant Prostate Cancer. New Engl J Med. (Accessed June 10, 2020, at https://www.nejm.org/doi/ suppl/10.1056/NEJMoa1800536/suppl_file/nejmoa1800536_appendix.pdf.)
- Fizazi K, Shore N, Tammela TL, Ulys A. Overall survival (OS) results of phase III ARAMIS study of darolutamide (DARO) added to androgen deprivation therapy (ADT) for nonmetastatic castration-resistant prostate cancer (nmCRPC). J Clin Oncol 2020;38 suppl;abstr 5514.
- Small EJ, Saad F, Chowdhury S, et al. Final survival results from SPARTAN, a phase III study of apalutamide (APA) versus placebo (PBO) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC). J Clin Oncol 2020;38:5516-.
- Sternberg CN, Fizazi K, Saad F, et al. Enzalutamide and Survival in Nonmetastatic, Castration- Resistant Prostate Cancer. N Engl J Med 2020;382:2197-206.
- Clinical Research Protocol: PROSPER: A Multinational, Phase 3, Randomized, Double-Blind, Placebo-Controlled, Efficacy and Safety Study of Enzalutamide in Patients With Nonmetastatic Castration-Resistant Prostate Cancer. 2017. (Accessed June 10 2020, at https://clinicaltrials.gov/ ProvidedDocs/24/NCT02003924/Prot_000.pdf.)
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- Iacovelli R, Ciccarese C, Bria E, et al. The Cardiovascular Toxicity of Abiraterone and Enzalutamide in Prostate Cancer. Clin Genitourin Cancer 2018;16:e645-e53.
- Beer TM, Shore ND, Morgans AK, et al. DaroACT: Darolutamide and enzalutamide effects on physical and neurocognitive function and daily activity in patients with castration-resistant prostate cancer (CRPC). J Clin Oncol 2020;38:TPS5587-TPS.
- Smith MR, Saad F, Hussain M, et al. ARASENS: A phase 3 trial of darolutamide in combination with docetaxel for men with metastatic hormone-sensitive prostate cancer (mHSPC). J Clin Oncol 2018;36:TPS383-TPS.