Clinical trialPhase 3Prostate cancer

Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer

N Engl J Med · 20221306 patients

Smith MR, Hussain M, Saad F, Fizazi K, Sternberg CN, Crawford ED, et al. N Engl J Med. 2022. 386:1132-1142

Study type: Clinical trial
Study name: ARASENS
Phase: Phase 3
Design: International randomised, double-blind, placebo-controlled trial
Sample size: 1306 patients
Source: N Engl J Med · 2022
Trial registration: NCT02799602

In plain words

In men whose prostate cancer had already spread when it was first diagnosed, adding darolutamide tablets to hormone therapy and docetaxel chemotherapy reduced the risk of death by about one third, without a noticeable increase in side effects.

Key results

32.5%

Overall survival (reduction in risk of death)

HR 0.68; 95% CI 0.57–0.80; P<0.001

66.1% vs 63.5%

Grade 3 or 4 adverse events

Darolutamide vs placebo

33.7% vs 34.2%

Grade 3 or 4 neutropenia

Mainly during the period of overlap with docetaxel

Drugs in this study:Docetaxel (Taxotere)

Dose and schedule cards

Triplet therapy: ADT + docetaxel + darolutamide (ARASENS)

mHSPC (especially high-volume de novo disease) in patients suitable for docetaxel; ECOG 0 to 1; ADT started no more than 12 weeks before treatmentEach drug’s schedule in the tableOn the page “Prostate cancer” · Metastatic hormone-sensitive disease (mHSPC)

mHSPC (especially high-volume de novo disease) in patients suitable for docetaxel; ECOG 0 to 1; ADT started no more than 12 weeks before treatment

Drug	Dose	Route	Schedule
Darolutamide	600 mg (2 × 300-mg tablets) twice daily	Oral, with food	Daily, continuous
Docetaxel	75 mg/m²	IV, 1-h infusion	Day 1 every 21 days; first cycle within 6 weeks after starting darolutamide
ADT (GnRH agonist or antagonist, or prior orchiectomy)	Per formulation	—	Continuous

Cycle schedule: Darolutamide daily and continuously; docetaxel every 21 days (6 cycles); ADT continuous
Duration: 6 cycles of docetaxel; darolutamide until progression or toxicity (even if docetaxel is delayed or stopped)

Per the FDA label and the trial; in ARASENS, prednisone or prednisolone with docetaxel was at the physician’s discretion.

On the page “Prostate cancer” · Metastatic hormone-sensitive disease (mHSPC)

ARASENS

Metastatic hormone-sensitive prostate cancerOn the page “Darolutamide with docetaxel and hormone therapy (ARASENS)”

Metastatic hormone-sensitive prostate cancer

Drug	Dose	Route	Schedule
Hormone therapy (ADT)	GnRH agonist or antagonist, or surgical castration		Continuous
Darolutamide	600 mg twice a day	Oral, with food	Daily
6 cycles
Docetaxel	75 mg/m²	IV	Every 21 days

Cycle length: Darolutamide daily; docetaxel every 21 days
Duration: Darolutamide and ADT until progression; docetaxel 6 cycles

As in ARASENS; docetaxel within 6 weeks of starting ADT.

Dose source:.

On the page “Darolutamide with docetaxel and hormone therapy (ARASENS)”

Docetaxel + ADT (CHAARTED trial)

Metastatic hormone-sensitive prostate cancer (outside the FDA label)Each drug’s schedule in the tableOn the page “Docetaxel (Taxotere)” · Regimens and dosing

Metastatic hormone-sensitive prostate cancer (outside the FDA label)

Drug	Dose	Route	Schedule
Docetaxel	75 mg/m²	IV	Day 1, every 21 days
Androgen deprivation therapy (ADT)	As scheduled		Continuous

Cycle schedule: Docetaxel every 21 days (6 cycles); ADT continuous
Duration: 6 cycles

Dose from the CHAARTED trial. In ARASENS, darolutamide 600 mg twice daily was added to ADT and docetaxel.

On the page “Docetaxel (Taxotere)” · Regimens and dosing

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Darolutamide + ADT + docetaxel (651 patients)

Darolutamide 600 mg (two 300 mg tablets) orally twice daily with food, until progression or toxicity, plus ADT (LHRH agonist or antagonist or orchiectomy within 12 weeks before randomisation) and six cycles of docetaxel 75 mg/m² IV on day 1 every 21 days, started within 6 weeks after randomisation; prednisone or prednisolone at the physician's discretion (651 patients).

2Placebo + ADT + docetaxel (655 patients)

Matching placebo twice daily with the same ADT and six cycles of docetaxel 75 mg/m² every 21 days (655 patients).

Source of the regimen details: Full text of the paper (PMC9844551) and ClinicalTrials.gov NCT02799602

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

1306 men aged 18 years or older with metastatic hormone-sensitive prostate cancer (metastases on bone scan, CT or MRI) who were candidates for ADT and docetaxel, with ECOG performance status 0 or 1 and adequate bone marrow, hepatic and renal function; ADT had been started no more than 12 weeks before randomisation. 86.1% had metastatic disease at diagnosis (de novo); 78.2% Gleason 8 or higher. A significant cardiovascular event within the past 6 months was an exclusion criterion.

Endpoints

Primary endpoint: overall survival. Key secondary endpoints: time to castration-resistant prostate cancer, time to pain, time to symptomatic skeletal event and time to subsequent anticancer therapy.

Safety and side effects

Adverse events were similar in the two groups and occurred mostly during the period of concurrent docetaxel. Grade 3 or 4 adverse events: 66.1% versus 63.5%; neutropenia was the most common grade 3 or 4 adverse event (33.7% and 34.2%). Serious adverse events 44.8% versus 42.3%; grade 5 adverse events: 4.1% versus 4.0%. Discontinuation of darolutamide or placebo due to adverse events 13.5% versus 10.6%.

Clinical significance and place in guidelines

ARASENS led to FDA and EMA approval of darolutamide with docetaxel in mHSPC and made triplet therapy (ADT + docetaxel + darolutamide) a standard option in the EAU, ESMO and NCCN guidelines for patients fit for chemotherapy, especially those with high-volume disease.

Limitations

The control group did not receive an ARPI, so the contribution of docetaxel versus doublet ADT + ARPI was not directly examined; few patients had low-volume disease; some control patients did not receive optimal subsequent therapy after progression.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.