Background
Double-blind, phase 3 randomised clinical trial (SOLARIS; Alliance A021703; NCT04094688). N=455 patients with previously untreated metastatic colorectal cancer (mCRC), enrolled across the US National Clinical Trials Network from October 2019 to December 2022; database freeze July 15, 2024. Median age 59 y; 181 (40%) female. Designed as the confirmatory trial for the phase 2 SUNSHINE signal, in which high-dose vitamin D3 improved progression-free survival.
Results
Interventions and follow up: Arm A: mFOLFOX6 or FOLFIRI plus bevacizumab every 2 weeks + high-dose vitamin D3 (8,000 IU daily ×14 days as loading dose, then 4,000 IU daily), n=228
Arm B: Same chemotherapy plus bevacizumab + standard-dose vitamin D3 400 IU daily, n=227
Primary endpoint: Progression-free survival (PFS), unstratified log-rank test
mFollow up: 20 months. Treatment continued until progression, intolerable toxicity or withdrawal of consent.
Results: PFS (primary): 11.8 mo (95% CI 10.3–13.3) vs 10.3 mo (95% CI 9.4–12.2), 1-sided log-rank P=.25.
OS: 25.6 vs 27.0 mo, 1-sided log-rank P=.66.
ORR: 51% (95% CI 44–58) vs 44% (95% CI 37–50), P=.12.
Hazard ratios: NR in the primary report.
Prespecified subgroup PFS analyses by prognostic factors: performed; no differential effect reported.
Arm B: Same chemotherapy plus bevacizumab + standard-dose vitamin D3 400 IU daily, n=227
Primary endpoint: Progression-free survival (PFS), unstratified log-rank test
mFollow up: 20 months. Treatment continued until progression, intolerable toxicity or withdrawal of consent.
Results: PFS (primary): 11.8 mo (95% CI 10.3–13.3) vs 10.3 mo (95% CI 9.4–12.2), 1-sided log-rank P=.25.
OS: 25.6 vs 27.0 mo, 1-sided log-rank P=.66.
ORR: 51% (95% CI 44–58) vs 44% (95% CI 37–50), P=.12.
Hazard ratios: NR in the primary report.
Prespecified subgroup PFS analyses by prognostic factors: performed; no differential effect reported.
Adverse events
Grade ≥3 neutropenia: 32% (67) vs 30% (62).
Grade ≥3 hypertension: 20% (42) vs 23% (49).
Vitamin D-associated toxicity (hypercalcaemia, nephrolithiasis): no difference in incidence between groups.
Overall: no clinically meaningful differences in the most common grade ≥3 events between high-dose and standard-dose groups.
Discontinuation: NR.
Grade ≥3 hypertension: 20% (42) vs 23% (49).
Vitamin D-associated toxicity (hypercalcaemia, nephrolithiasis): no difference in incidence between groups.
Overall: no clinically meaningful differences in the most common grade ≥3 events between high-dose and standard-dose groups.
Discontinuation: NR.
Conclusions
High-dose vitamin D3 added to first-line chemotherapy plus bevacizumab did not improve PFS, OS or objective response in metastatic colorectal cancer. SOLARIS is an adequately sized, double-blind, cooperative-group phase 3 that fails to confirm the phase 2 SUNSHINE signal, and it removes the rationale for prescribing supraphysiologic vitamin D3 as an anticancer intervention in this setting.
Key Limitations
Median follow-up of 20 months is short relative to a roughly 26-month median OS, so overall survival is immature — though the point estimate numerically favoured the standard-dose arm, which makes a late reversal implausible. Baseline and on-treatment 25-hydroxyvitamin D concentrations are not reported in the primary abstract, so it is not established that the high-dose arm achieved a distinct biological exposure, nor whether vitamin D-deficient patients — the subgroup with the strongest observational rationale — were adequately represented. Chemotherapy backbone was investigator's choice (mFOLFOX6 or FOLFIRI), introducing heterogeneity. One-sided hypothesis testing. Molecular stratification (RAS/BRAF status, mismatch repair status, primary tumour sidedness) is not reported in the abstract. Findings apply to supraphysiologic dosing added to first-line therapy and say nothing about correcting frank vitamin D deficiency.
Clinical Context
Observational data have consistently linked higher circulating 25-hydroxyvitamin D concentrations with better colorectal cancer outcomes, and the phase 2 SUNSHINE trial (Ng et al, JAMA 2019; N=139) reported a PFS improvement with high-dose vitamin D3 — a finding that generated considerable patient demand and off-protocol prescribing. SOLARIS is the confirmatory phase 3 and is unambiguously negative. No major guideline (NCCN, ASCO or ESMO) recommends high-dose vitamin D3 as antineoplastic therapy in metastatic colorectal cancer, and SOLARIS should settle the question and support de-implementation of supraphysiologic dosing for that purpose. Repletion of documented vitamin D deficiency for skeletal and general-health indications is a separate matter and is unaffected by this trial.