Adding Darolutamide: New SOC for Metastatic Prostate Cancer

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New data suggest that adding darolutamide (Nubeqa) onto androgen deprivation therapy (ADT) and docetaxel should become a new standard of care for men with metastatic hormone-sensitive prostate cancer (mHSPC), say investigators reporting results from the phase 3 ARASENS study.

The three drug combination significantly reduced the risk of death by 32.5% (hazard ratio [HR], 0.68; P < .001) vs ADT plus docetaxel. After 4 years, 62.7% of the darolutamide group vs 50.4% of the placebo were still alive.  

The addition of darolutamide also led to improvement in key secondary endpoints, including the time to reach castration-resistant prostate cancer, when the disease becomes more difficult to treat.

The new results were presented here at the 2022 Genitourinary Cancers Symposium, and simultaneously published in The New England Journal of Medicine to coincide with the meeting.

“Based on these findings, darolutamide in combination with ADT and docetaxel should become a new standard of care for treatment of mHSPC,” said lead author Matthew Smith, MD, PhD, director of the Genitourinary Malignancies Program, Massachusetts General Hospital Cancer Center, Boston.

Discussant for the study, Elisabeth Heath, MD, associate center director of Translational Sciences and leader of the Genitourinary Oncology Multidisciplinary Team at Karmanos Cancer Institute, Detroit, agreed.

“ADT, docetaxel, and darolutamide is the new standard of care due to increased overall survival in men with mHSPC,” Heath commented in her discussion. “Patient characteristics to consider for a combination therapy approach include M1b and M1c disease stage and fitness for combination treatment.”

The ARASENS study  has “provided us with a new standard of care, a triplet, for the right patients,” she commented.

Enzalutamide in mCRPC

Heath also discussed another abstract presented at the same session. This was also metastatic prostate cancer, but a slightly different patient population. The phase 3 PRESIDE trial was conducted in men with metastatic castration-resistant prostate cancer (mCRPC) who had progressed on enzalutamide (Xtandi).

The results showed that patients who continued on enzalutamide plus docetaxel and prednisone achieved superior progression-free survival (PFS) vs placebo with docetaxel and prednisone.

The median PFS was significantly longer in the enzalutamide group at 9.5 months vs 8.2 months for placebo (P = .027).

“The secondary endpoints of time to PSA progression and PSA response data supported the PFS findings,” commented lead author Axel S. Merseburger, MD, PhD, chairman of the Clinic of Urology at University Hospital Schleswig-Holstein in Lübeck, Germany.

Taken together, these data suggest that “continued treatment with enzalutamide plus docetaxel offers clinical benefit and could be a future treatment option for some patients who progress on enzalutamide alone,” he said

In her discussion of the paper, Heath said that PRESIDE provides a new treatment option, “where you can at least know some of the side effects and offer it to the right patient.”

As for the take-home message from the PRESIDE study, Heath emphasized that while this regimen is a new treatment option, it is not a standard of care. “But would I be comfortable in knowing that the patient who has responded to enzalutamide continues to have a clinical benefit, but has some slight progression, and may have some improvement in PFS by 28% and offering that with docetaxel? Yes,” she said.

Commenting on both of the new trials together, she said that there are now translational implications to figure out, as far as navigating these new data and putting them into clinical practice. “We need to encourage a multidisciplinary team approach to improve treatment strategies, and consider disease burden and other factors to optimize treatment, ” Heath said. “We all have to have the same plan and strategy for our patients.”

Details of the ARASENS Study

The ARASENS study included 1306 patients with mHSPC who were randomly assigned to receive darolutamide at 600 mg twice daily (n = 651) or placebo (n = 654), combined with ADT and docetaxel.

All patients had metastatic disease at baseline; 79.5% had bone metastases (metastasis stage M1b) and 17.5% had visceral metastases (metastasis stage M1c). Additionally, most patients (86.1%) had metastatic disease at their time of initial diagnosis.

At the time of data cutoff, darolutamide had significantly decreased the risk of death and improved overall survival (4-year overall survival rate was 62.7% vs 50.4%), and the survival benefit of darolutamide was observed across most subgroups.

“This significant improvement in overall survival was observed despite a high percentage of patients who received subsequent life-prolonging systemic therapies,” said Smith.

Darolutamide also significantly delayed the development CRPC and time to pain progression. The median time to CRPC was 19.1 months for placebo vs not reached for the darolutamide arm (HR, 0.36; P < .001), and the median time to pain progression was 27.5 vs not reached (HR, 0.79; P = .01).

Treatment-related adverse events were similar in the two groups, and the incidences of the most common events (≥ 10%) were highest during the overlapping docetaxel treatment period for both arms. Grade 3/4 events occurred in 66.1% of patients in the darolutamide arm and 63.5% in the placebo group. The most common adverse event was neutropenia (33.7% and 34.2%, respectively).

Details of the PRESIDE Trial

The PRESIDE trial was divided into two parts: part 1 enrolled chemotherapy-naive men with mCRPC and disease progression received enzalutamide  (160 mg) and ADT. Those who had a PSA response of  ≥ 50% change from baseline to week 13 and later progression were eligible participate in the second part.

A total of 273 patients were enrolled in part 2 of the trial, and randomly assigned to either enzalutamide at 160 mg per day or matched placebo, docetaxel at 75 mg/m2 every 3 weeks, and prednisone at 10 mg daily.  Treatment continued until disease progression.

The study met its primary endpoint of superior PFS in the enzalutamide group.

For secondary endpoints, time to PSA progression (≥ 25% increase; absolute increase ≥ 2 ng/mL) was delayed for 8.4 months in the enzalutamide group compared with 6.2 months for placebo (HR, 0.58; P = .002). PSA response was also improved at any time (55.9% vs 37%).

For other measures, the objective response rate also favored the enzalutamide group (31.6% vs 25.9%) and complete responses were also higher (19.1% vs 12.6%).

“Results for a post-hoc analysis illustrated the PFS benefit in subgroups,” said Merseburger, noting that the largest benefit was seen in patients with metastasis to soft tissue and bone and visceral disease.

Grade 3/4 adverse events were reported by 61.8% of patients in the enzalutamide group and 62.2% on placebo, and 8.8% and 6.7% of patients, respectively, experienced events that led to discontinuation. “Enzalutamide combined with docetaxel retained an acceptable safety profile that was consistent with the known individual safety profiles of these drugs,” said Merseburger.

The ARASENS study was funded by Bayer and Orion Pharma. Smith, Merseburger, and Heath all reported relationships with numerous pharmaceutical companies, as detailed on the abstracts.

Genitourinary Cancers Symposium (GUCS) 2022: Abstracts 13 (ARASENS) and 14 (PRESIDE), both presented February 18, 2022.

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