Darolutamide Cuts Metastasis Risk 58 Percent but OS and Approval Path Unproven

Bayer's Nubeqa Combination Shows Strong MFS in DASL-HiCaP Study

The DASL-HiCaP study, presented at the European Society of Medical Oncology (ESMO) congress 2026, investigated darolutamide (Bayer's Nubeqa) combined with radiotherapy and androgen deprivation therapy (ADT) against radiotherapy plus ADT in 1,106 patients with very high-risk localised prostate cancer. At a median follow-up of 3.8 years, the interim analysis demonstrated a 58% reduction in the risk of metastasis or death with the darolutamide combination. The study reported a four-year metastasis-free survival based on conventional imaging (MFS-CI) rate of 95% for the combination arm, compared to 88% in the comparator arm, suggesting a potential overall survival benefit.

• The DASL-HiCaP study demonstrated a significant 58% reduction in the risk of metastasis or death for patients with very high-risk localised prostate cancer treated with darolutamide, radiotherapy, and ADT. This combination achieved a four-year metastasis-free survival rate of 95%, substantially higher than the 88% observed in the control arm, highlighting its potent anti-metastatic activity.
• The study's primary endpoint, metastasis-free survival based on conventional imaging (MFS-CI), is considered a reliable surrogate for overall survival, suggesting a likely long-term survival benefit. Additionally, significant improvements were observed in secondary endpoints, including prostate-specific antigen progression-free survival (HR 0.47; 95% CI 0.33–0.67) and time to subsequent hormonal therapy (HR 0.36; 95% CI 0.22–0.59), reinforcing the comprehensive benefits of the darolutamide regimen.
• The positive DASL-HiCaP data broadens the potential patient populations for Nubeqa, extending its utility beyond previously approved indications in castrate-resistant and metastatic hormone-sensitive prostate cancer. Bayer continues to investigate darolutamide in other prostate cancer trials, such as ARASTEP (NCT05794906), exploring its potential in high-risk biochemical recurrence.

DASL-HiCaP: Darolutamide's Impact in Very High-Risk Localised Prostate Cancer

Selected high-risk localized prostate cancer studies evaluate intensified radiotherapy approaches combined with varying durations of androgen deprivation therapy. Designs range from randomized phase 3 trials to retrospective multi-institutional comparisons, with endpoints focused on biochemical control, metastasis, and survival.

Nubeqa's Expanding Reach Across the Prostate Cancer Spectrum

Darolutamide-based radiotherapy combinations are being explored across earlier-stage and metastatic prostate cancer beyond very high-risk localised disease. The literature describes a randomized trial in unfavorable intermediate-risk disease and a real-world multimodal approach in metastatic hormone-sensitive prostate cancer (mHSPC) incorporating PSMA-guided focal treatment.

• Unfavorable intermediate-risk prostate cancer in the DARIUS (AFU-GETUG P15) Phase 2 trial: The DARIUS trial is a multicenter randomized non comparative phase 2 trial randomizing 6-months darolutamide + EBRT arm versus 6-months ADT + EBRT in patients with unfavorable intermediate-risk PCa. Sixty-two patients will be included, with combination of androgen deprivation therapy (ADT) with external beam radiation therapy (EBRT) described as a standard of care for patients with intermediate-risk prostate cancer (PCa).

• DARIUS intervention model and endpoints: The primary endpoint is a biological response defined as prostate-specific antigen ≤0.1 ng/ml at month six of darolutamide or ADT. The key secondary endpoints are biochemical recurrence-free survival, disease-free survival, safety, and QoL, with ancillary studies using radiomics and genomic classifier planned.

• Metastatic hormone-sensitive prostate cancer with PSMA imaging-guided focal treatment: This multicenter, retrospective study included 17 patients treated across three tertiary hospitals between June 2023 and June 2024. All patients received darolutamide (600 mg twice daily), ADT, and docetaxel (75 mg/m every 3 weeks for 4-6 cycles), followed 4-6 weeks later by focal therapy (surgery or radiotherapy) based on multidisciplinary team (MDT) assessment and PSMA IMAGING findings.

A Dynamic Landscape: New Advances in Prostate Cancer Treatment

Neoadjuvant systemic therapy before radical prostatectomy remains investigational, with no phase 3 data supporting its use and no recommendation for routine practice in international guidelines. The National Comprehensive Cancer Network guidelines strongly discourage the use of ADT as a neoadjuvant therapy outside of clinical trials. Early neoadjuvant trials of first-generation androgen deprivation therapy improved pathological findings including pT3, positive surgical margins and lymph node involvement, and reduced tumour volume, but did not improve biochemical recurrence or other hard oncological end points such as cancer-related death. Renewed interest has focused on addition of androgen receptor signaling inhibitors including abiraterone, apalutamide, enzalutamide and darolutamide, and on androgen receptor pathway inhibitors, which have revealed pathological downstaging, biological activity, and favorable pCR, MRD, PSA relapse and salvage therapy rates in phase-II trials.

Comparative and early-phase trial data suggest potential activity for intensified neoadjuvant regimens but remain hypothesis-generating. In a comparative analysis of 112 patients treated on 3 trials of neoadjuvant novel hormonal agent followed by radical prostatectomy versus 259 patients undergoing up-front radical prostatectomy, after inverse probability of treatment weighting time to biochemical recurrence (HR=0.25 [95% CI 0.18-0.37]) and metastasis-free survival (HR=0.26 [0.15-0.46]) were significantly longer in the neo-RP cohort, with rates of adjuvant (7% vs 24%) and salvage therapy (34% vs 46%) lower in the neo-RP cohort. A phase I/II trial of neoadjuvant radiation therapy and docetaxel before prostatectomy in 25 men with high-risk prostate cancer used 45 Gy radiotherapy in 25 fractions to the prostate and seminal vesicles over 5 weeks with weekly dose-escalated docetaxel up to 30 mg/m²; the primary endpoint of pathologic complete response was not achieved, lymphopenia was the most common grade 3 or higher toxicity with no grade 3 or higher genitourinary or gastrointestinal toxicities observed, and with median follow-up of 11.6 years the 10-year biochemical recurrence-free survival was 60%, distant metastasis-free survival was 80%, prostate cancer-specific survival was 84% and overall survival was 60%. In a phase 2 trial of 24 months of leuprolide and enzalutamide with 5 weeks of intensity modulated radiation therapy followed by brachytherapy boost in high-risk localized or regional nonmetastatic patients, all patients achieved PSA complete response defined as PSA ≤0.3 with median time to PSA-CR of 4.2 months, 0 of 11 (0%) patients had biochemical recurrence at 24 months and 1 of 9 (11.1%) had biochemical recurrence at 36 months, with 1 of 11 (9%) grade 4 adverse event (seizure) and 4 of 11 (36.4%) grade 3 adverse events.

Safety signals have tempered enthusiasm for some local intensification strategies, while definitive phase 3 evaluation is pending. A single-institution phase 1 trial (NCT02946008) of neoadjuvant stereotactic body radiotherapy (30-35 Gy/5 fractions to prostate and seminal vesicles and 25 Gy/5 fractions to pelvic lymph nodes) followed by radical prostatectomy was stopped early (n=16 of planned 38 patients) owing to proportion and severity of late adverse events, with post-RP grade 3 genitourinary toxicities in 75% (n=12) and gastrointestinal toxicities in 25% (n=4), 2 patients requiring cystectomy and urinary diversion ≥2 years post-RP, and 3-year biochemical recurrence of 45% (95% CI, 5%-68%) and distant metastasis of 28% (95% CI, 0%-49%). Chemotherapy with docetaxel is feasible with some evidence of long-term benefit but data for short-term endpoints remain inconclusive, and radioligand therapy with [Lu]-labelled prostate-specific membrane antigen ligands and genomically guided approaches are feasible and safe but remain exploratory. The phase 3 PROTEUS trial (NCT03767244) will determine the impact of androgen receptor pathway inhibitors as neoadjuvant therapy on survival, and ongoing large-scale trials will be critical to define the role of neoadjuvant therapy in clinical practice.

Darolutamide's DASL-HiCaP Data: Reshaping Localized Prostate Cancer Care

The DASL-HiCaP study's findings for darolutamide in very high-risk localised prostate cancer represent a pivotal moment in the disease's management. For years, androgen deprivation therapy (ADT) has been the cornerstone of systemic treatment, with newer androgen receptor inhibitors (ARIs) like darolutamide primarily making their mark in later stages, such as nonmetastatic castration-resistant prostate cancer (nmCRPC) and metastatic hormone-sensitive prostate cancer (mHSPC). This new data, demonstrating a remarkable 58% reduction in the risk of metastasis or death when darolutamide is added to radiotherapy and ADT, pushes the envelope for treatment intensification into an earlier, potentially curative setting.

This shift is significant because preventing metastasis is a critical goal in prostate cancer care. The 95% four-year metastasis-free survival rate observed with the darolutamide combination, compared to 88% with standard therapy, underscores a profound clinical benefit that could translate into improved overall survival. A key advantage for darolutamide in this long-term adjuvant setting is its established favorable safety profile. Research indicates that darolutamide generally has a lower incidence of certain adverse events, such as hypertension and cardiac disorders, compared to other ARIs. This tolerability is crucial for patients undergoing prolonged treatment, enhancing adherence and maintaining quality of life.

However, this advancement also brings considerations for clinical teams and strategic planners:

• Long-term safety: While generally well-tolerated, the cumulative effects of darolutamide, ADT, and radiotherapy over many years, particularly concerning risks like bone fractures and hypertension, warrant ongoing monitoring.

• Patient stratification: The precise identification of 'very high-risk localised' patients is critical. The increasing sensitivity of advanced imaging like PSMA-PET could redefine what constitutes 'localised' disease, potentially impacting patient selection for this intensified regimen.

• Competitive dynamics: The prostate cancer landscape is highly competitive. While darolutamide has a strong new data point, continuous innovation and comparative effectiveness studies will be essential to maintain its position against other ARIs and emerging therapies. This study sets a new benchmark, signaling a future where earlier, more aggressive, and better-tolerated systemic therapies become the standard for preventing disease progression in high-risk localised prostate cancer.