What is the recommended treatment approach for combining Stereotactic Body Radiation Therapy (SBRT) with Nubeqa (darolutamide) for patients with non-metastatic castration-resistant prostate cancer or high-risk localized prostate cancer?

SBRT Combined with Nubeqa (Darolutamide) for Prostate Cancer

Current evidence does not support combining SBRT with darolutamide (Nubeqa) as a standard treatment approach, as no clinical trials have evaluated this specific combination and existing guidelines do not recommend it. The available evidence addresses darolutamide primarily in non-metastatic castration-resistant prostate cancer (nmCRPC) and metastatic hormone-sensitive disease, while radiation therapy recommendations exist separately for localized and locally advanced disease.

Evidence for Darolutamide Use

Darolutamide is FDA-approved specifically for nmCRPC with rapid PSA doubling time (≤10 months), not for combination with SBRT in localized disease. 1, 2

• The ARAMIS trial demonstrated that darolutamide significantly prolonged metastasis-free survival in nmCRPC patients with PSADT ≤10 months (HR 0.41 for PSADT ≤6 months; HR 0.38 for PSADT >6 months) 1
• Darolutamide showed favorable tolerability with low incidence of adverse events including fractures, falls, hypertension, and mental impairment compared to other androgen receptor inhibitors 1
• The drug is being studied in metastatic hormone-sensitive disease combined with docetaxel (ARASENS trial), not with radiation therapy 2, 3

Current Guideline-Based Radiation Approaches

For high-risk localized prostate cancer requiring radiation, ASCO guidelines recommend EBRT with long-term ADT (24-36 months), not novel androgen receptor inhibitors like darolutamide. 4

• External beam radiation therapy using IMRT techniques with doses of 78-80+ Gy is the standard approach for high-risk disease 4
• Image-guided radiation therapy (IGRT) is required for doses ≥78 Gy 4
• Pelvic lymph node irradiation should be considered for high-risk patients 4

ASCO guidelines specifically recommend ADT plus abiraterone (not darolutamide) for noncastrate locally advanced nonmetastatic disease when combined with radiation. 5

• ADT plus abiraterone and prednisolone demonstrated failure-free survival benefit in the STAMPEDE trial for nonmetastatic disease (strong recommendation, high-quality evidence) 5
• Radiation therapy to the primary was mandated in STAMPEDE for node-negative nonmetastatic disease 5

Why This Combination Lacks Evidence

The clinical development pathway for darolutamide has focused on castration-resistant disease and metastatic hormone-sensitive disease, not on combination with definitive local therapy like SBRT. 2, 3

• Darolutamide trials (ARAMIS, ARASENS) enrolled patients with either nmCRPC or metastatic hormone-sensitive disease, not candidates for primary radiation therapy 2, 3
• No published trials have evaluated darolutamide combined with SBRT or any form of radiation therapy 1, 6, 2
• The EMBARK trial mentioned in guidelines evaluates enzalutamide (not darolutamide) with ADT in high-risk nonmetastatic disease after RP or RT, but results are not yet available 5

Alternative Evidence-Based Approaches

For patients requiring both systemic therapy and radiation, use established combinations rather than experimental approaches:

For High-Risk Localized Disease:

• EBRT (78-80 Gy) plus long-term ADT (24-36 months) is the standard of care 4
• Consider adding brachytherapy boost to EBRT for improved disease control (HR 0.77 for disease-specific mortality) 4
• ADT plus abiraterone can be considered for locally advanced nonmetastatic disease per STAMPEDE 5

For nmCRPC After Prior Local Therapy:

• Darolutamide 600 mg twice daily with continued ADT is appropriate for patients with PSADT ≤10 months who have already completed definitive therapy 1, 2
• This represents sequential therapy (radiation first, then darolutamide at progression), not concurrent combination 1

Critical Caveats

Attempting to combine SBRT with darolutamide outside of a clinical trial would be off-label use without safety or efficacy data. 2, 3

• Cross-resistance between androgen receptor inhibitors exists, though darolutamide may retain activity after enzalutamide or apalutamide failure in some patients (55.5% PSA response rate in small series) 6
• The distinct chemical structure of darolutamide compared to other AR inhibitors does not justify empiric combination with SBRT without trial data 6, 7
• Cost considerations are significant, as darolutamide would add substantial expense to radiation therapy without proven benefit 7

If considering novel combinations for high-risk disease, prioritize enrollment in clinical trials rather than empiric off-label use. 3