Neal D. Shore, MD1; Alberto Martini, MD2; Pedro Barata, MD, MSc3
1START Carolinas and AUC Urology Specialists, Myrtle Beach, South Carolina
2 Department of Urology, University of Cincinnati College of Medicine, Cincinnati, Ohio
3 University Hospitals Seidman Cancer Center, Cleveland, Ohio
KEYWORDS:
Prostatic neoplasms; urology; medical oncology
Abstract
Background: Metastatic hormone-sensitive prostate cancer (mHSPC) presents a substantial health and economic burden to patients and health systems. Despite an initial response to androgen-deprivation therapy (ADT), patients with mHSPC ultimately progress and need additional therapy for optimal disease control. Although doublet and triplet regimens including androgen receptor pathway inhibitors have demonstrated survival benefits, ADT monotherapy remains common in mHSPC.
Methods: Darolutamide is a highly potent androgen receptor inhibitor with low blood-brain barrier penetration and low potential for drug-drug interactions. Positive results from the ARAMIS (darolutamide and ADT) trial in nonmetastatic castration-resistant prostate cancer and the ARASENS (darolutamide with ADT and docetaxel) trial in mHSPC provide the rationale for evaluating darolutamide and ADT in patients with mHSPC in ARANOTE.
Results: ARANOTE showed statistically significant and clinically meaningful improvement in radiographic progression-free survival for patients who received darolutamide with ADT compared with ADT alone, leading to the approval of darolutamide doublet therapy for this indication. The ARANOTE study also confirmed favorable safety and tolerability of darolutamide compared with other androgen receptor pathway inhibitors.
Conclusions: Based on results of ARANOTE, doublet therapy with darolutamide and ADT is a US Food and Drug Administration–approved treatment option for patients with mHSPC across disease severities. Clinicians should consider factors such as accessibility, cost, and therapeutic inertia when initiating darolutamide in mHSPC.
Prostate cancer is a frequently occurring and burdensome cancer among men in the United States.1,2 Aside from skin cancer, prostate cancer is the most common malignancy among men in the United States, with approximately 313 780 new cases and 35 770 deaths estimated in 2025.1 Most prostate cancers (70%) are found at a localized stage, but approximately 14% are found at a regional stage and 8% at a distant stage.2 In previous decades, prostate cancer death rates declined, probably reflecting earlier disease detection and treatment innovations. However, in recent years the death rate decline has slowed, possibly because of the rise in prostate cancers being found at an advanced stage.1
Despite reductions in prostate cancer death rates, the incidence of metastatic prostate cancer is increasing.3 Although metastatic hormone-sensitive prostate cancer (mHSPC) can be treated with androgendeprivation therapy (ADT) to deprive prostate cancer cells of growth-stimulating androgens, it is generally considered to be incurable.3 The 5-year survival rate of patients with metastatic castration-resistant prostate cancer (mCRPC) is estimated to be approximately 30%, compared with 5-year survival rates of 100% for those with localized prostate cancer.3,4
In addition, mHSPC presents a greater health and economic burden than nonmetastatic disease to patients and health systems.5 Patients with mHSPC have a poor prognosis and worse health-related quality of life with disease progression, incurring greater costs and health care utilization than patients with nonmetastatic hormone-sensitive prostate cancer.6 On average, most patients with mHSPC progress to mCRPC within 1 year.7,8 Despite advances in treatment of mHSPC in recent years, the optimal care of these patients continues to evolve. This article reviews the current treatment landscape for mHSPC, including unmet treatment needs, and the phase 3 ARANOTE study, which provided the evidence base for an expanded indication for darolutamide, a novel androgen receptor inhibitor for patients with advanced prostate cancer.
The standard of care for mHSPC for decades has been ADT, which provides beneficial clinical outcomes such as rapid clinical improvement for patients with symptomatic disease.9 Surgical or pharmacologic ADT can result in palliation of painful bony metastases, decreases in postvoid residual urine, and improved quality of life for patients with mHSPC, although the clinical benefits must be considered in the context of the well-described testosterone suppression side effects.9 Moreover, despite an initial response to ADT, progression ultimately occurs, and additional therapies are needed for optimal disease control.9-11
In the past 10 to 15 years, systemic treatment has evolved from ADT alone or combined with firstgeneration antiandrogen to doublet therapy that consists of ADT and docetaxel or ADT and a secondgeneration androgen receptor pathway inhibitor.12 The shift from ADT monotherapy to combination therapy in mHSPC originated with the CHAARTED and STAMPEDE trials, showing survival benefit for ADT and docetaxel compared with ADT alone in patients with mHSPC.8,13 However, not all patients are fit for docetaxel, often because of coexisting conditions or patient preferences. For men with synchronous, low-volume mHSPC, radiation to the prostate provides a survival benefit consistent with results of the STAMPEDE trial.12,14
The combination of ADT and an androgen receptor pathway inhibitor has been investigated in multiple trials, leading to the approval of doublet therapies with abiraterone acetate, apalutamide, darolutamide, and enzalutamide.12 Abiraterone was studied in STAMPEDE, LATITUDE, and PEACE-1, indicating an overall survival benefit in patients receiving ADT with abiraterone and prednisone compared with ADT alone.15-17 The androgen receptor inhibitor apalutamide was evaluated in the TITAN trial, and enzalutamide was evaluated in the ENZAMET and ARCHES trials, with statistically significant overall survival benefits observed for patients with mCRPC receiving an androgen receptor inhibitor vs ADT alone.18-20 Until recently in the ARANOTE trial (discussed in detail later in this report), darolutamide was not tested as a doublet regimen for mHSPC.21
The selection of patients who should receive triplet vs doublet regimens for mHSPC remains under debate as research seeks to clarify who would benefit from chemotherapy as part of the regimen.12 It remains critical to identify patients with mHSPC who would benefit from highly intensified initial therapy up front while accounting for potential toxicities.12 Data for triplet regimens come from the ARASENS, PEACE-1, and ENZAMET trials; collective data and metaanalyses support initiating therapy with an androgen receptor inhibitor, ADT, and docetaxel, particularly for patients with synchronous, high-volume metastatic disease.17,22-24
Consistent with additional survival benefits observed with doublet and triplet therapy, clinical practice guidelines for mHSPC recommend offering ADT in combination with androgen pathway–directed therapy or chemotherapy for most patients.10,11
However, despite the benefits of doublet and triplet regimens seen in clinical trials, many patients with mHSPC continue to receive ADT alone25 because of various barriers in clinical practice, such as problems with accessibility and tolerability, concerns about safety and drug interactions, and shortcomings in clinician education.25-28 Ultimately, these clinical practice gaps demonstrate a need to optimize approaches that delay progression of mHSPC to mCRPC with acceptable shared decision-making.21
Darolutamide is a highly potent androgen receptor inhibitor, structurally distinct from other agents, which has demonstrated low blood-brain barrier penetration in preclinical models and low potential for drug-drug interactions. This pharmacokinetic profile may be advantageous for patients with mHSPC, who often have age-related comorbidities and polypharmacy needs.21 ARAMIS and ARASENS are 2 trials that tested darolutamide in patients with advanced prostate cancer as part of doublet and triplet therapy, respectively.22,29,30
The ARAMIS trial was a phase 3 trial in patients with nonmetastatic castration-resistant prostate cancer in which darolutamide plus ADT showed statistically significantly longer metastasis-free survival and overall survival than ADT alone.30 The ARASENS trial was a phase 3 trial in which patients with mHSPC were randomly assigned to darolutamide plus ADT and docetaxel or placebo plus ADT and docetaxel.22 Results showed that darolutamide plus ADT and docetaxel reduced the risk of mortality by 32.5% and statistically significantly delayed progression to mCRPC compared with placebo plus ADT and docetaxel.22 These outcomes persisted regardless of disease volume and prognostic risk subgroups.29
In ARASENS and ARAMIS, the incidence of adverse events and treatment discontinuations caused by adverse events was similar between darolutamide and placebo, highlighting the long-term tolerability of darolutamide and providing the rationale for the ARANOTE trial.22,29,30 In June 2025, the US Food and Drug Administration approved a new indication for darolutamide based on the phase 3 ARANOTE trial: for the treatment of adult patients with mHSPC. Previously, darolutamide was approved for mHSPC only in combination with docetaxel.21,31
The ARANOTE study was a global, randomized, double-blind, placebo-controlled phase 3 trial that evaluated darolutamide as part of a doublet regimen for mHSPC.21 The objective of the phase 3 ARANOTE trial was to assess the efficacy and safety of darolutamide plus ADT without chemotherapy in patients with mHSPC.21
Patients in ARANOTE were recruited from 133 sites in 15 countries, with a plan to enroll 665 patients.21 Patients were eligible if they were 18 years of age or older and had histologically or cytologically confirmed prostate adenocarcinoma and metastatic disease, which was confirmed centrally by conventional imaging.21 Additional key inclusion criteria included21
ECOG-ACRIN performance status 0-2;
adequate bone marrow, liver, and kidney function; and
could have started ADT within 12 weeks of random assignment.
Patients were excluded from the study if they had only regional lymph node metastases, if they had a baseline superscan, or if they had previously received an androgen receptor pathway inhibitor or chemotherapy for treatment of prostate cancer.21
Eligible patients for ARANOTE started investigator’s choice ADT (orchiectomy or luteinizing hormonereleasing hormone agonist) within 12 weeks before starting study treatment.21 After receiving ADT, patients were randomly assigned 2:1 to darolutamide 600 mg orally twice daily or a matched placebo. Participants were stratified based on the use of prior local therapy.21
The primary end point was radiographic progressionfree survival (rPFS).21 The study was designed around this end point and not to detect overall survival differences between study groups, justifying the smaller sample size. Secondary end points included21
overall survival;
time to initiation of subsequent systemic anticancer therapy for prostate cancer;
time to progression to mCRPC;
time to prostate-specific antigen progression; and
time to pain progression.
Of 889 patients screened, 669 were randomly assigned: 446 to receive darolutamide and 223 to receive placebo, both with ADT.21 A total of 666 patients (darolutamide, n = 445; placebo, n = 221) were included in the safety analysis.21 Baseline demographic and disease characteristics were well balanced between the treatment groups (Table 1).21 Median treatment duration was 24.2 months in the darolutamide group and 17.3 months in the placebo group; median follow-up time was 25.3 months and 25.0 months, respectively.21
The primary end point (rPFS) was evaluated after 222 patients had an event; a smaller proportion of patients in the darolutamide group (128 of 446 [28.7%]) experienced rPFS compared with placebo (94 of 223 [42.2%]).21 Patients receiving darolutamide had statistically significantly higher rPFS, with a 46% lower risk of radiological progression or death than placebo (hazard ratio, 0.54 [95% CI, 0.41-0.71]; P < .001) (Figure 1).21 Median rPFS was not reached in those receiving darolutamide, and it was 25.0 months in the placebo group.21 At 24 months, rPFS rates were 70.3% in the darolutamide group and 52.1% in the placebo group, and the benefit of darolutamide on rPFS was consistent across prespecified patient subgroups, which included patients with high-volume mHSPC and low-volume mHSPC.21
Secondary end point results (Table 2) showed a numeric benefit of darolutamide for overall survival and statistically significant benefit for time to initiation of subsequent systemic anticancer therapy, time to mCRPC (Figure 2), time to prostate-specific antigen progression (Figure 3), and time to pain progression.21
Figure 1. Kaplan-Meier estimates of rPFS in ARANOTE Abbreviations: ADT, androgen-deprivation therapy; NR, not reached; rPFS, radiographic progression-free survival. Reproduced from Saad et al. Journal of Clinical Oncology, 42(36), 4271-4281. Used with permission from Wolters Kluwer Health (Copyright ©2024). This article is available under the Creative Commons CC-BY-NC-ND license and permits noncommercial use of the work as published, without adaptation or alteration provided the work is fully attributed (https://creativecommons.org/licenses/).
Figure 2. Time to mCRPC in ARANOTE Abbreviations: ADT, androgen-deprivation therapy; NR, not reached. Reproduced from Saad et al. Journal of Clinical Oncology, 42(36), 4271-4281. Used with permission from Wolters Kluwer Health (Copyright ©2024). This article is available under the Creative Commons CC-BY-NC-ND license and permits noncommercial use of the work as published, without adaptation or alteration provided the work is fully attributed (https://creativecommons.org/licenses/).
Adverse events were similar between the darolutamide and placebo groups (Table 3), with most adverse events being grade 1 or 2 (darolutamide 55%, placebo 54.3%).21 Grade 3 or 4 adverse events occurred in approximately 30.8% of patients in the darolutamide group and 30.3% in the placebo group; the frequency of death caused by adverse events was low and similar between the 2 groups.21
Patients who received darolutamide plus ADT in ARANOTE experienced statistically significant and clinically meaningful rPFS improvement compared with those who received ADT alone. A favorable hazard ratio for overall survival was seen, though it was not statistically significant. These results, in addition to clear clinical benefits observed in other secondary end points, indicate that darolutamide and ADT may have a positive impact on the quality of life for patients with mHSPC.21 Of note, a recent analysis suggests a strong correlation between rPFS and overall survival in mHSPC, suggesting the reliability of rPFS as a surrogate end point in this context.32
The ARANOTE study also confirmed the favorable safety and tolerability of darolutamide that was seen in ARAMIS and ARASENS. Adverse events commonly associated with androgen receptor pathway inhibitors (including apalutamide or enzalutamide) can be burdensome to patients, and darolutamide had a lower incidence of these adverse events.21 In addition, ARANOTE is the first study of an androgen receptor antagonist that showed a lower incidence of fatigue in the treatment group (5.6%) than in the placebo group.21
Figure 3. Time to prostate-specific antigen progression in ARANOTE Abbreviations: ADT, androgen-deprivation therapy; NR, not reached; PSA, prostate-specific antigen. Reproduced from Saad et al. Journal of Clinical Oncology, 42(36), 4271-4281. Used with permission from Wolters Kluwer Health (Copyright ©2024). This article is available under the Creative Commons CC-BY-NC-ND license and permits noncommercial use of the work as published, without adaptation or alteration provided the work is fully attributed (https://creativecommons.org/licenses/).
The use of placebo plus ADT as the comparator is a potential limitation of the ARANOTE trial because ADT monotherapy is not considered a standard of care for mHSPC.21 The prevalence of ADT-only monotherapy to treat mHSPC remains high, with US studies in the past decade reporting rates of at least 50%. Within the past 2 to 3 years, however, some data suggest lower rates, ranging from 20% to 36%; ADT monotherapy remains a common real-world comparator for clinical trials.33,34 Clinicians will need to address barriers to successful therapy implementation, such as cost, therapeutic inertia, and treatment familiarity considerations. Along with other androgen pathway receptor inhibitors, darolutamide is typically a higher-cost treatment that may have limited access and formulary restrictions for many patients. In addition, darolutamide is taken orally twice daily, which may be a concern for adherence in patients who prefer less frequent dosing.
Although prostate cancer and specifically mHSPC remain burdensome to patients and the health care system, new advances in treatment continually improve the management of this disease. Monotherapy with ADT has historically been the standard of care for mHSPC, but now evidence suggests that doublet and triplet regimens that include an androgen pathway receptor inhibitor or chemotherapy are preferable for most patients.
The phase 3 ARANOTE study showed a statistically significant benefit of darolutamide plus ADT compared with placebo plus ADT in patients with mHSPC, consistent across high-volume and low-volume disease and other patient subgroups. Darolutamide had tolerability comparable to that of placebo and was favorable compared with other androgen receptor pathway inhibitors. Based on the results of ARANOTE, darolutamide received a new US Food and Drug Administration–approved indication for the treatment of patients with mHSPC. This suggests it can be used as a doublet therapy (in combination with ADT) as well as a component of triplet therapy. As with most newer treatments, clinicians will need to address barriers to therapy such as accessibility, cost, and therapeutic inertia when initiating darolutamide in mHSPC.
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Published: October 5, 2025.
Conflict of Interest Disclosures: N. D. Shore serves or has served as a consultant for Accord, Alessa, Amgen, Antev, Arquer, Asieris, Astellas, AstraZeneca, Aura Biosciences, Bayer, Bioprotect, Bristol Myers Squibb, CG Oncology, Clarity, Dendreon, Exact Imaging, Ferring, Fize Medical, Glytherix, Invitae, Janssen, Lantheus, Lilly, MDxHealth, Merck, Minomic, Myriad, Novartis, Pfizer, Photocure, Platformq, Preview, Promaxo, Propella, Protara, Sanofi Genzyme, Siemens, Specialty Networks, Sumitomo, Telix, Tolmar, Tutelix, and UroGen. P. Barata reports grants and personal fees from Astellas, AstraZeneca, Bayer, Guardant Health, Bristol Myers Squibb, Caris Life Sciences, Dendreon, Eisai, EMD Serono, ESSA Pharma, Exelixis, Ipsen, Janssen, Merck, Merus, Myovant, OncLive, Pfizer, Seattle Genetics, Targeted Oncology, and UroToday not related to this work. A. Martini has no financial relationships to disclose.
Funding/Support: Funding for this review was provided by Bayer; however, the content was solely that of the authors.
Author Contributions: All authors had final responsibility for the decision to submit for publication.
Data Availability Statement: No proprietary data were used in the development of this article. All materials used to prepare the manuscript are cited within the text and reference list.
Acknowledgments: The authors thank Austin Ulrich, PharmD, BCACP, of Dragonfly Editorial for medical writing assistance in preparing the manuscript.
Citation: Shore ND, Martini A, Barata P. The data behind a new mHSPC indication for darolutamide: a review of the phase 3 ARANOTE study. Rev Urol. 2025;24(3):e23-e33.
Corresponding author: Neal D. Shore, MD, 823 82nd Pkwy, Suite B, Myrtle Beach, SC 29572 (nshore@auclinics.com)
