Darolutamide Crossover Leads to High PSA Response in Nonmetastatic CRPC


Eighty-five percent of patients with nonmetastatic castration-resistant prostate cancer who crossed over from placebo to darolutamide in the phase 3 ARAMIS trial experienced a maximum prostate-specific antigen decline of at least 50% at any time of crossover.

Susan Feyerabend, MD

Susan Feyerabend, MD

Eighty-five percent of patients with nonmetastatic castration-resistant prostate cancer (CRPC) who crossed over from placebo to darolutamide (Nubeqa) in the phase 3 ARAMIS trial (NCT02200614) experienced a maximum prostate-specific antigen (PSA) decline of at least 50% at any time of crossover, according to analysis presented at the 2021 European Association of Urology Congress.1

At 16 weeks after crossover, at which time 149 patients had PSA value, 58.4% of patients had a PSA decline of at least 90%, 89.9% had a PSA decline of at least 50%, and 93.3% of patients had a PSA decline of at least 30%. Five patients (3.4%) did not experience any PSA decline.

“In 170 patients who received darolutamide following crossover from placebo, the clinical benefit of PSA response and safety profile were consistent with those observed in the randomized darolutamide patients,” lead study author Susan Feyerabend, MD, of the Department of Uro-Oncology, Studienpraxis Urologi, in Nuertingen, Germany, said in a virtual presentation during the meeting.

Darolutamide is a structurally distinct androgen receptor inhibitor that is approved by the FDA for the treatment of patients with nonmetastatic CRPC. The July 2019 approval was based on earlier findings from the double-blind, phase 3 ARAMIS trial, in which 1509 patients with nonmetastatic CRPC and a PSA doubling time of 10 months or less were randomized 2:1 to received darolutamide at 600 mg twice daily plus androgen deprivation therapy (ADT; n = 955) or placebo twice daily plus ADT (n = 554).

Results of the primary analysis, which had a cutoff date of September 3, 2018, showed that the agent had demonstrated significantly prolonged metastasis-free survival (MFS) and overall survival (OS) in men with nonmetastatic CRPC. Data demonstrated that darolutamide in combination with ADT led to a 59% reduction in the risk of metastases or death compared with placebo/ADT in this patient population (HR, 0.41; 95% CI, 0.34-0.50; 2-sided, P <.0001).2,3

In January 2021, the FDA approved a supplemental new drug application to add OS data, as well as other secondary end point data, from ARAMIS to darolutamide’s label for the nonmetastatic CRPC indication. Here, darolutamide led to a 31% reduction in the risk of death, extending survival for patients with nonmetastatic CRPC (HR, 0.69; 95% CI, 0.53-0.88; = .003).4 The additional findings comprise time to pain progression (HR, 0.65; 95% CI, 0.53-0.79; <.0001) and time to the initiation of cytotoxic chemotherapy (HR, 0.58; 95% CI, 0.44-0.76; <.0001).

After the unblinding of the ARAMIS trial occurred on November 30, 2018, 170 patients who were initially on the placebo arm crossed over to the darolutamide arm during the open-label period. In the 2021 EAU Congress presentation, investigators highlighted the clinical benefit and safety of darolutamide in the crossover population.

In the open-label period, 466 patients continued on darolutamide treatment; on the placebo arm, patients went on to receive subsequent therapy with darolutamide (n = 170) or another life-prolonging therapy (n = 137).

For patients who crossed over to receive darolutamide at the final analysis cutoff, PSA outcomes were used to assessed clinical benefit as the duration of therapy was not long enough to assess either MFS or OS. Crossover baseline value served as the last outcome measurement before crossover from placebo to darolutamide.

Furthermore, investigators noted that adverse effects (AEs) that were reported during the double-blind period were compared with the crossover period for the same observation time; this was consistent with the median treatment duration in crossover patients.

Regarding baseline characteristics, patients who crossed over from placebo to darolutamide had higher median PSA values (19.8 ng/mL; range, 0.0-786.9) at the start of darolutamide treatment compared with that of study entry (7.1 ng/mL; range, 1.6-116.7). These patients also had poorer ECOG performance status (≥1, 31%) vs 25.3% for patients at study entry.

The median treatment duration for patients who crossed over to darolutamide was 11.0 months (range, 1-12).

Additionally, results showed that the median PSA values declined from 19.8 ng/mL at crossover baseline to 0.9 ng/mL at the nadir during the open-label period.

Regarding safety, similar or lower rates of AEs, serious AEs, and AEs that led to treatment discontinuation were reported in the crossover group compared with the double-blind treatment period with darolutamide. Any-grade AEs occurred in 70.0% of crossover patients compared with 75.8% and 71.8% for double-blind darolutamide and placebo, respectively. Serious AEs occurred in 15.3% of crossover patients, 14.8% of double-blind darolutamide-treated patients, and 12.3% of double-blind placebo-treated patients. Grade 3/4 AEs occurred in 15.9% of both crossover and double-blind darolutamide-treated patients and 13.7% of double-blind placebo patients.

On the crossover-to-darolutamide arm, 7.1% of patients and 4.7% of patients experienced AEs leading to dose reductions/dose interruptions and permanent treatment discontinuation, respectively. On the double-blind darolutamide arm, these rates were 9.6% and 5.9%; the rates were 7.0% and 4.7% on the double-blind placebo arm.

Feyerabend noted that most AEs of interest were lower in the crossover group compared with the darolutamide double-blind period, including fatigue (4.1% with crossover vs 10.8% with double-blind darolutamide vs 7.6% with double-blind placebo), hypertension (1.8% vs 4.9% vs 5.1%, respectively), fall (2.4% vs 2.5% vs 3.2%), bone fracture (2.9% vs 2.5% vs 2.0%), rash (2.4% vs 2.2% vs 1.1%), and mental impairment disorder (0% vs 1.2% vs 1.3%).

At the 2021 Genitourinary Cancers Symposium, additional crossover data from ARAMIS showed that crossover from placebo to darolutamide in patients with nonmetastatic CRPC appeared have a minimal impact on OS benefit observed with darolutamide.5


  1. Feyerabend S, Shore N, Smith M, et al. Clinical benefit and safety profile of darolutamide in patients who crossed over to darolutamide from placebo during the open-label period of the phase 3 ARAMIS study. Presented at: 2021 EAU Congress; July 8-12, 2021; virtual. Abstract P1227.
  2. Fizazi K, Shore ND, Tammela T, et al. ARAMIS: efficacy and safety of darolutamide in nonmetastatic castration-resistant prostate cancer (nmCRPC). J Clin Oncol. 2019;37(suppl 7s; abstr 140). doi:10.1200/JCO.2019.37.7_suppl.140
  3. Fizazi K, Shore N, Tammela T, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Eng J Med. 2019;380(13):1235-1246. doi: 10.1056/NEJMoa1815671.
  4. Nubeqa (darolutamide tablets). Prescribing information. Bayer; 2021. Accessed January 8, 2021.
  5. Shore ND, Fizazi K, Tammela T, et al. Analysis of the effect of crossover from placebo (PBO) to darolutamide (DARO) on overall survival (OS) benefit in the ARAMIS Trial. J Clin Oncol. 2021;39(suppl 6; abstr 240). doi:10.1200/JCO.2021.39.6_suppl.240

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