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US MEDICAL AFFAIRS

Nubeqa® (Darolutamide)
Sequencing with Enzalutamide

SUMMARY

  • No prospective randomized studies have been identified in the published literature which specifically evaluate the sequencing of darolutamide and enzalutamide.
  • The ARAMIS study (NCT02200614) was a randomized, double-blind (DB), placebo-controlled phase 3 study (N=1509) which evaluated the efficacy and safety of darolutamide + androgen deprivation therapy (ADT; n=955) vs placebo + ADT (n=554) in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). Subsequent therapy was permitted at the discretion of the principal investigator.1,2
    • Patients were excluded from enrollment if they had prior treatment with a second-generation androgen receptor inhibitor (ARI), such as enzalutamide.3
    • At the final analysis (median follow-up for the overall population, 29.0 months), in the darolutamide group, 28 (3%) patients subsequently received enzalutamide as a life-prolonging therapy. No efficacy or safety outcomes were reported for these patients.2
  • The ARASENS study (NCT02799602) was an international, randomized, DB, placebo-controlled, phase 3 study (N=1306) which evaluated the efficacy and safety of darolutamide + ADT + docetaxel (n=651) vs placebo + ADT + docetaxel (n=655) in patients with metastatic, hormone-sensitive prostate cancer (mHSPC).4
    • Patients were excluded from enrollment if they had prior treatment with a second-generation ARI, such as enzalutamide.5
    • Among darolutamide patients who entered active or long-term follow-up for survival (n=315), 48 (15.2%) patients subsequently received enzalutamide as a life-prolonging therapy.5 A post-progression analysis based on first subsequent anticancer therapy has been published.6

This page is intended for US healthcare professionals and may contain information outside of the approved prescribing information. It is provided in response to an unsolicited request. It is not intended as an endorsement of any usage not contained in the Prescribing Information. This response should be reviewed together with the current full Prescribing Information (including Boxed Warning) and Medical Safety Summary. These materials contain the approved indications, contraindications, warnings and precautions, adverse reactions, and other important safety information for Nubeqa® (Darolutamide).

Nubeqa is an androgen receptor inhibitor indicated for the treatment of adult patients with non-metastatic castration-resistant prostate cancer (nmCRPC), metastatic castration-sensitive prostate cancer (mCSPC), and metastatic castration-sensitive prostate cancer (mCSPC) in combination with docetaxel.

 

  • The ARANOTE study (NCT04736199; N=669) was an international, randomized, DB, placebo-controlled phase 3 study which evaluated darolutamide + ADT (n=446) vs placebo + ADT (n=223) in patients with mHSPC.7 
    • Patients were excluded from enrollment if they had prior treatment with a second-generation ARI, such as enzalutamide.8
    • Of the 203 (45.5%) patients treated with darolutamide who discontinued treatment, 6 (3.0%) received subsequent enzalutamide treatment.7
  • The ARASEC study (NCT05059236) was a United States (US), prospective, open-label phase 2 study which evaluated the efficacy and safety of darolutamide + ADT in patients with mHSPC vs an external control arm of patients treated with ADT alone in the CHAARTED study (n=160 in each group; matched 1:1 using propensity scores).9
    • Of the 42 ARASEC patients with a mCRPC event, 5 (11.9%) received subsequent abiraterone and/or enzalutamide as life-prolonging therapy.
  • The SAKK 08/16 study (NCT02933801) was a randomized, DB, placebo-controlled phase 2 study (N=90) which evaluated darolutamide maintenance therapy in patients with metastatic castration-resistant prostate cancer (mCRPC). Patients were previously treated with enzalutamide and/or abiraterone for ≥8 weeks and had stable disease after subsequent taxane therapy. Previous treatment with enzalutamide and/or abiraterone was one of the stratification factors.10
    • Baseline characteristics were generally well balanced in both the darolutamide (n=45) and placebo (n=45) groups. In either group, 60%, 31%, and 9% of patients had previously received abiraterone, enzalutamide, or both, respectively.
    • The proportion of patients with radiographic progression-free survival (rPFS) at 12 weeks after treatment start (primary endpoint), was 64.7% (95% confidence interval [CI], 47.6%-77.5%) in the darolutamide group and 52.2% (95% CI, 36.1%-66.1%) in the placebo group (estimated difference, 12.5%; 1-sided 85% CI, 1.1%; 1-sided P=0.127). For darolutamide vs placebo, other secondary endpoints including median rPFS, event-free survival (EFS), and overall survival (OS) were 5.5 vs 4.5 months (hazard ratio [HR], 0.54 [95% CI, 0.32-0.91]; P=0.017), 5.4 vs 2.9 months (HR, 0.46 [95% CI, 0.29-0.73]; P<0.001), and 24.0 vs 21.3 months (HR, 0.62 [95% CI, 0.3-1.26]; P=0.181), respectively.
    • A subgroup analysis of patients who had a prior response (complete or partial) to latest enzalutamide or abiraterone (n=29) showed a statistically significant improvement with darolutamide vs placebo for rPFS (HR, 0.35 [95% CI, 0.14-0.87]; P=0.019), and the HR for OS was 0.26 (95% CI, 0.06-1.19; P=0.063). In patients with prior stable or progressive disease (n=61), HR was 0.7 (95% CI, 0.36-1.35; P=0.28) for rPFS and 0.97 (95% CI, 0.39-2.43; P=0.95) for OS.
      • No significant difference in rPFS or OS according to prior use enzalutamide was found (HR, 0.36 [95% CI, 0.12-1.07]).
    • Grade 1, 2, and 3 treatment-related adverse events, respectively, were observed in 26%, 13%, and 2% of patients in the darolutamide group (n=46) and 22%, 15%, and 2% of patients in the placebo group (n=46).

LITERATURE SEARCH

A literature search of Embase®, PubMed, and/or other resources, including internal/external databases, was conducted pertaining to this topic on 11 June 2026. Included in this response are data from prospective clinical studies.

 

REFERENCES

 

All the references were accessed on the abovementioned literature search date.

 

  1. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med. 2019;380(13):1235–1246. PMID: 30763142 https://www.ncbi.nlm.nih.gov/pubmed/30763142
  2. Fizazi K, Shore N, Tammela TL, et al. Nonmetastatic, Castration-Resistant Prostate Cancer and Survival with Darolutamide. N Engl J Med. 2020;383(11):1040–1049. PMID: 32905676 https://www.ncbi.nlm.nih.gov/pubmed/32905676
  3. Protocol for: Fizazi K, Shore N, Tammela TL, et al. Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med. 2019;380(13):1235–1246. Accessed via https://www.nejm.org/doi/suppl/10.1056/NEJMoa1815671/suppl_file/nejmoa1815671_pr otocol.pdf
  4. Smith MR, Hussain M, Saad F, et al. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. N Engl J Med. 2022;386(12):1132–1142. PMID: 35179323 https://www.ncbi.nlm.nih.gov/pubmed/35179323
  5. Supplement to: Smith MR, Hussain M, Saad F, et al. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. N Engl J Med. 2022;386(12):1132–1142. Accessed via https://www.nejm.org/doi/suppl/10.1056/NEJMoa2119115/suppl_file/nejmoa2119115_ap pendix.pdf
  6. Grimm MO, Smith M, Hussain M, et al. Postprogression Survival of Patients with Metastatic Hormone-sensitive Prostate Cancer who Received Darolutamide or Placebo in Combination with Docetaxel and Androgen Deprivation Therapy: Post Hoc Analysis of the Phase 3 ARASENS Trial. Eur Urol. 2025;PMID: 40544121 https://www.ncbi.nlm.nih.gov/pubmed/40544121
  7. Saad F, Vjaters E, Shore N, et al. Darolutamide in Combination With AndrogenDeprivation Therapy in Patients With Metastatic Hormone-Sensitive Prostate Cancer From the Phase III ARANOTE Trial. J Clin Oncol. 2024;42(36):4271–4281. PMID: 39279580 https://pubmed.ncbi.nlm.nih.gov/39279580/
  8. Protocol to: Saad F, Vjaters E, Shore N, et al. Darolutamide in Combination With Androgen-Deprivation Therapy in Patients With Metastatic Hormone-Sensitive Prostate Cancer From the Phase III ARANOTE Trial. J Clin Oncol. 2024:Jco2401798. Accessed via https://ascopubs.org/action/downloadSupplement?doi=10.1200%2FJCO-24- 01798&file=protocol_JCO-24-01798.pdf
  9. McKay R, Ross AE, Preston MA, et al. Darolutamide plus ADT in mHSPC: ARASEC US prospective, open-label phase 2 study with an external control arm. Oral Presentation presented at: American Urological Association (AUA) Annual Meeting; May, 15–18, 2026; Washington, DC.
  10. Gillessen S, Procopio G, Hayoz S, et al. Darolutamide Maintenance in Patients With Metastatic Castration-Resistant Prostate Cancer With Nonprogressive Disease After Taxane Treatment (SAKK 08/16). J Clin Oncol. 2023;41(20):3608–3615. PMID: 36753698 https://www.ncbi.nlm.nih.gov/pubmed/36753698
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Site last updated 09/2026

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