High-Dose Vitamin D in Metastatic Colorectal Cancer: What the SOLARIS Trial Found

National Cancer Institute medical illustration of the colon and rectum with surrounding digestive organs and nearby lymph nodes; illustrative image, not a SOLARIS trial participant or study specimen.

Soleil Research™ | Evidence Review

Original study: Ng K, Ou F-S, Zemla T, et al. Addition of High-Dose Vitamin D3 to Standard Treatment in Patients With Metastatic Colorectal Cancer: The SOLARIS Randomized Clinical Trial (Alliance A021703). JAMA. 2026;336(9):746–754. doi:10.1001/jama.2026.9350.

Plain-Language Summary

In the phase 3 SOLARIS trial, 455 adults with previously untreated metastatic colorectal cancer received standard first-line chemotherapy plus bevacizumab and were randomly assigned to high-dose or standard-dose vitamin D3. High-dose vitamin D3 did not significantly prolong progression-free survival. Objective response rate and overall survival were also not significantly different, and major toxicity was broadly similar between groups.

Why This Study Matters

Vitamin D has long attracted interest in colorectal cancer because of biologic and epidemiologic signals, and an earlier phase 2 trial had suggested that higher-dose supplementation might improve progression-free survival. SOLARIS was designed as the larger, confirmatory phase 3 test of that hypothesis.

This distinction is important: promising mechanistic reasoning and phase 2 signals can justify a definitive trial, but they do not substitute for phase 3 evidence.

What the Study Tested

SOLARIS was a double-blind, multicenter, randomized phase 3 trial conducted through the U.S. National Clinical Trials Network. A total of 455 patients with previously untreated metastatic colorectal cancer were randomized 1:1.

All participants received mFOLFOX6 or FOLFIRI plus bevacizumab every 2 weeks. The experimental group received vitamin D3 8,000 IU daily for 14 days as a loading dose followed by 4,000 IU daily. The control group received 400 IU daily. Treatment continued until disease progression, unacceptable toxicity, or withdrawal.

The prespecified primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate, overall survival, and toxicity. The trial was prospectively registered as NCT04094688.

What the Study Found

After a median follow-up of 20 months:

  • Median PFS: 11.8 months with high-dose vitamin D3 versus 10.3 months with standard-dose vitamin D3 (1-sided log-rank P=.25).
  • Objective response rate: 51% versus 44%, respectively (P=.12).
  • Median overall survival: 25.6 months versus 27.0 months, respectively (1-sided log-rank P=.66).
  • Safety: no clinically meaningful differences were reported in the most common grade 3 or higher adverse events or in vitamin D–associated toxicities.

The primary endpoint was therefore neutral. The study did not demonstrate that high-dose vitamin D3 added to this chemotherapy-plus-bevacizumab regimen improves progression-free survival.

Methodological Quality

Overall assessment: HIGH — confirmatory phase 3 randomized evidence.

The trial directly addressed a clinically relevant treatment question using randomization, double blinding, a multicenter National Clinical Trials Network setting, a prespecified primary endpoint, prospective registration, and clinically meaningful secondary outcomes. These features substantially reduce selection and ascertainment bias and make the neutral primary result important.

One methodological point deserves attention: PFS and overall survival were evaluated using prespecified 1-sided log-rank tests. A 1-sided test is less conservative than the more commonly used 2-sided framework because it tests for benefit in a specified direction. Even under that design, the primary result was not statistically significant.

Strengths

  • Phase 3 confirmatory design following an earlier encouraging phase 2 signal.
  • Randomized, double-blind allocation with 455 participants.
  • Multicenter conduct through the U.S. National Clinical Trials Network.
  • Clearly defined dosing contrast between high-dose and standard-dose vitamin D3.
  • Clinically meaningful primary and secondary outcomes, including PFS, overall survival, response, and toxicity.
  • Prospective trial registration and prespecified subgroup analyses.

Limitations and Cautions

  • The trial evaluated high-dose vitamin D3 specifically with mFOLFOX6 or FOLFIRI plus bevacizumab. Its results should not automatically be generalized to other systemic regimens, including anti-EGFR treatment strategies.
  • JAMA's research summary notes that unmeasured use of additional vitamin D supplements could not be fully excluded.
  • Prespecified subgroup findings can generate hypotheses, but they should not override a neutral primary endpoint without independent confirmation.
  • The study was conducted in the United States, so generalizability to populations and treatment systems outside the trial setting is not unlimited.
  • A neutral superiority trial does not prove that the two vitamin D strategies are biologically identical or rule out every small treatment effect; it means the prespecified trial did not demonstrate the hypothesized PFS benefit.

Funding and Conflicts of Interest

JAMA reports funding from the National Cancer Institute of the National Institutes of Health and Pharmavite LLC. The published conflict-of-interest statement reports that lead author Kimmie Ng received institutional nonfinancial support from Pharmavite and Janssen and personal fees from multiple companies outside the submitted work. Several coauthors also reported consulting, research, advisory, travel, or other relationships with pharmaceutical and diagnostics companies; no other disclosures were reported.

These disclosures are relevant to transparency. They do not by themselves invalidate the trial, and the randomized, double-blind design provides important protection against several common sources of bias.

Soleil Insight

Biological plausibility is a reason to test a treatment—not a reason to assume it works.

SOLARIS is a useful example of why confirmatory trials matter. An earlier phase 2 signal justified a rigorous phase 3 study. The larger trial then produced a neutral primary result. For the regimen studied, high-dose vitamin D3 should therefore not be presented as an evidence-based add-on for improving metastatic colorectal cancer outcomes.

The correct scientific response to a neutral phase 3 trial is neither disappointment nor dismissal. It is refinement: preserve the result, narrow the claim, and let the prespecified primary endpoint anchor interpretation.

Original Publication

Ng K, Ou F-S, Zemla T, et al. Addition of High-Dose Vitamin D3 to Standard Treatment in Patients With Metastatic Colorectal Cancer: The SOLARIS Randomized Clinical Trial (Alliance A021703). JAMA. 2026;336(9):746–754. doi:10.1001/jama.2026.9350

Trial registration: NCT04094688

Featured Image Attribution

“Colon and Rectum,” medical illustration by Alan Hoofring for the National Cancer Institute. Public domain. The image is illustrative and does not depict a SOLARIS trial participant or study specimen.

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Soleil Research™ provides educational scientific analysis and does not provide individual medical diagnosis or treatment advice.