What is the recommended treatment for non-metastatic castration-resistant prostate cancer using Nubeqa (darolutamide)?

Nubeqa (Darolutamide) for Non-Metastatic Castration-Resistant Prostate Cancer

Darolutamide 600 mg (two 300 mg tablets) orally twice daily with food is the recommended treatment for patients with non-metastatic castration-resistant prostate cancer (nmCRPC) who have a PSA doubling time ≤10 months, while continuing androgen deprivation therapy (ADT). 1, 2

Indication and Patient Selection

Darolutamide is a Category 1, preferred option for nmCRPC patients with PSADT ≤10 months. 1 This recommendation is based on the pivotal ARAMIS trial, which demonstrated substantial mortality and morbidity benefits in this population. 1

Key Eligibility Criteria:

• Non-metastatic castration-resistant prostate cancer confirmed by imaging 1
• PSA doubling time of 10 months or less 1, 2
• Ongoing ADT (GnRH analog or bilateral orchiectomy) 2

Importantly, darolutamide provides significant benefit even in patients with PSADT >6 months (up to 10 months), not just those with the highest-risk PSADT ≤6 months. 3 This distinguishes the evidence base from assumptions that only the fastest-progressing patients benefit.

Dosing and Administration

The FDA-approved dosing regimen is darolutamide 600 mg (two 300 mg tablets) twice daily, taken with food. 2 Tablets must be swallowed whole. 2

Dose Modifications:

• Severe renal impairment (not on hemodialysis): Reduce to 300 mg twice daily 2
• Moderate hepatic impairment: Reduce to 300 mg twice daily 2

Efficacy Outcomes: Mortality and Morbidity Benefits

The ARAMIS trial provides robust evidence for darolutamide's impact on the outcomes that matter most:

Overall Survival:

Darolutamide reduced the risk of death by 31% compared to placebo (HR 0.69; 95% CI 0.53-0.88; P=0.003). 1 At 3 years, overall survival was 83% with darolutamide versus 77% with placebo. 1

Metastasis-Free Survival:

**Darolutamide more than doubled metastasis-free survival: 40.4 months versus 18.4 months with placebo (HR 0.41; 95% CI 0.34-0.50; P<0.001).** 1, 4 This benefit was consistent across both PSADT subgroups (>6 months: HR 0.38; ≤6 months: HR 0.41). 3

Quality of Life Preservation:

Darolutamide significantly delayed time to pain progression and maintained quality of life without disruptions. 3, 4 This is a critical advantage, as the goal in nmCRPC is to delay progression while preserving functional status.

Safety Profile: A Distinguishing Feature

Darolutamide demonstrates a remarkably favorable safety profile compared to other androgen receptor inhibitors, with adverse event rates similar to placebo. 1, 4

Key Safety Advantages:

• Fracture rate similar to placebo: 4.2% versus 3.6% 1
• No increased risk of falls, seizures, cognitive disorders, or hypertension compared to placebo 4
• Discontinuation rate due to adverse events: 8.9% versus 8.7% with placebo 4

Most Common Adverse Reactions:

• Fatigue: 12.1% versus 8.7% placebo 1
• Pain in extremity: 5.8% versus 3.2% placebo 1
• Rash: 2.9% versus 0.9% placebo 1

This safety profile is attributed to darolutamide's unique molecular structure, which provides high androgen receptor affinity without significant off-target effects. 5

Important Warnings and Precautions

Ischemic Heart Disease:

Optimize cardiovascular risk factor management and monitor for coronary artery disease symptoms; discontinue for Grade 3-4 cardiac events. 2

Seizure Risk:

Consider discontinuation if seizures develop during treatment. 2 However, the incidence was not higher than placebo in clinical trials. 4

Embryo-Fetal Toxicity:

Males with female partners of reproductive potential must use effective contraception during treatment and for 1 week after the last dose. 2

Drug Interactions

Avoid Concomitant Use:

• Combined P-gp and strong/moderate CYP3A inducers 2
• BCRP substrates where possible (if used together, monitor closely and consider dose reduction of BCRP substrate) 2

Monitor More Frequently:

• Combined P-gp and strong CYP3A inhibitors 2
• OATP1B1 and OATP1B3 substrates (may increase plasma concentrations; consider dose reduction) 2

Comparative Context with Other Agents

While apalutamide and enzalutamide are also Category 1, preferred options for nmCRPC with PSADT ≤10 months 1, darolutamide's distinguishing feature is its superior tolerability profile with comparable efficacy. 5

Apalutamide is associated with higher rates of rash (24%), fractures (11%), and hypothyroidism (8%). 1 Enzalutamide carries increased risks of fatigue (33%), hypertension (12%), major adverse cardiovascular events (5%), and mental impairment disorders (5%). 1

Clinical Decision-Making Algorithm

For patients with nmCRPC and PSADT ≤10 months:

1. Confirm eligibility: Non-metastatic disease on imaging, PSADT ≤10 months, ongoing ADT 1, 2

2. Assess patient factors:

   • If concerns about falls, fractures, or cognitive function: Darolutamide is preferred given its placebo-like safety profile 4, 5
   • If cardiovascular comorbidities: Darolutamide shows no increased hypertension or cardiovascular events versus placebo 4
   • If history of seizures: All three agents require caution, but darolutamide showed no increased seizure risk in trials 4

3. Initiate darolutamide 600 mg twice daily with food, continuing ADT 2

4. Monitor: Imaging every 16 weeks for metastasis detection, cardiovascular symptoms, and routine safety assessments 4

Common Pitfalls to Avoid

• Do not restrict darolutamide to only PSADT ≤6 months: Significant benefit extends to PSADT >6 months up to 10 months 3
• Do not forget dose adjustments: Reduce to 300 mg twice daily for severe renal impairment or moderate hepatic impairment 2
• Do not take without food: Administration with food is required 2
• Do not assume all androgen receptor inhibitors have similar safety profiles: Darolutamide's tolerability is distinctly superior 4, 5