High-dose vitamin D3 did not significantly delay cancer progression when added to standard first-line treatment for metastatic colorectal cancer, according to the phase 3 SOLARIS randomized clinical trial published in JAMA. The study enrolled 455 adults with previously untreated metastatic colorectal cancer and tested whether substantially increasing vitamin D3 exposure could improve outcomes beyond chemotherapy, bevacizumab and a standard vitamin D dose.
SOLARIS tested vitamin D as an add-on cancer treatment
Vitamin D has attracted sustained interest in cancer research because laboratory experiments and observational studies have suggested links between vitamin D signaling and tumor biology. Higher circulating vitamin D levels have also been associated with better outcomes in some studies of colorectal cancer, although observational associations cannot establish that giving more vitamin D changes the course of established cancer.
That distinction matters. Questions about vitamin D as a cancer treatment are different from questions about vitamin D deficiency, bone health or cancer prevention. We recently examined similar limits in the evidence around vitamin D and other supplements, where the biological effect depends heavily on population, baseline status and the outcome being measured.
SOLARIS, formally Alliance A021703, was designed to test treatment efficacy directly. Participants had advanced or metastatic colorectal adenocarcinoma that had not previously been treated systemically for metastatic disease. Patients with known mismatch repair-deficient or microsatellite instability-high tumors were excluded.
All participants received standard chemotherapy with either modified FOLFOX6 or FOLFIRI plus bevacizumab every two weeks. They were then randomly assigned, under double-blind conditions, to high-dose or standard-dose vitamin D3.
The high-dose group received 8,000 international units (IU) daily for 14 days, followed by 4,000 IU daily. The comparison group received 400 IU daily. Treatment continued until cancer progression, unacceptable toxicity or withdrawal.
The trial did not meet its primary endpoint
The primary endpoint was progression-free survival, the length of time patients remained alive without their cancer worsening. After a median follow-up of about 20 months, median progression-free survival was 11.8 months in the high-dose vitamin D3 group and 10.3 months in the standard-dose group.
The numerical difference did not reach statistical significance. The hazard ratio for progression or death was 0.92, with a 95% confidence interval from 0.73 to 1.16, and the prespecified one-sided log-rank test produced a P value of .25. In other words, the trial did not show that high-dose vitamin D3 reduced the risk of progression or death compared with the standard dose.
The same pattern appeared in other major outcomes. The objective response rate was 51% with high-dose vitamin D3 and 44% with the standard dose, a difference that was not statistically significant. Median overall survival was 25.6 months in the high-dose group and 27.0 months in the standard-dose group, again with no significant difference.
These results are especially useful because randomized trials can answer questions that observational studies cannot. As with research into obesity and cancer risk, associations in population studies can identify biologically plausible relationships, but they do not prove that changing a single exposure will improve cancer outcomes.
The Phase 3 result did not confirm the earlier Phase 2 signal
SOLARIS was launched because an earlier randomized phase 2 study called SUNSHINE had produced an encouraging signal. In SUNSHINE, 139 patients with advanced or metastatic colorectal cancer received chemotherapy plus either high-dose or standard-dose vitamin D3.
Median progression-free survival in that study was 13.0 months with high-dose vitamin D3 and 11.0 months with the standard dose. The primary log-rank comparison was not statistically significant, but an adjusted analysis produced a statistically significant hazard ratio that supported moving the strategy into a larger confirmatory trial.
SOLARIS was that confirmatory test. With 455 randomized participants, its failure to reproduce a significant progression-free survival benefit weakens the case for adding high-dose vitamin D3 to first-line treatment for metastatic colorectal cancer.
This is one reason promising Phase 2 findings need larger Phase 3 trials before changing clinical practice. Smaller studies can identify real signals, but they can also overestimate effect sizes or produce findings that do not hold up when tested in a broader population.
Higher doses changed vitamin D exposure, but not cancer outcomes
The negative result was not explained by poor adherence. Mean adherence to vitamin D3 was 96% in both groups, according to the JAMA report.
Blood measurements also showed that the trial meaningfully separated vitamin D exposure between the groups. At baseline, median plasma 25-hydroxyvitamin D concentrations were in the insufficient range in both groups. During treatment, levels remained significantly higher in the high-dose group than in the standard-dose group.
That makes the result more informative: investigators successfully raised vitamin D exposure, but the higher exposure did not translate into a statistically significant improvement in progression-free survival or overall survival.
The finding also illustrates a broader principle in translational cancer research. Biological plausibility does not guarantee clinical benefit. The same challenge appears in areas such as circulating tumor DNA and liquid biopsy, where a biomarker can be strongly associated with disease biology while the clinical value of acting on that information still has to be demonstrated prospectively.
High-dose vitamin D did not produce a major new safety signal
The investigators reported no clinically meaningful difference in the most common grade 3 or higher adverse events between groups. Neutropenia occurred in 31.6% of safety-evaluable patients receiving high-dose vitamin D3 and 29.7% receiving the standard dose. Hypertension occurred in 19.8% and 23.4%, respectively.
The study also did not identify a meaningful excess of toxicities typically associated with vitamin D. That is useful safety information, but safety alone does not justify an ineffective treatment. The central question was whether high-dose vitamin D3 improved cancer control, and the trial did not demonstrate that benefit.
A possible left-sided tumor signal remains exploratory
Prespecified subgroup analyses examined whether the treatment effect differed across clinical characteristics. Investigators reported a possible signal among patients with left-sided primary tumors, which include cancers arising from the splenic flexure through the rectum.
That observation should not be treated as proof of benefit. Subgroup findings can arise by chance, particularly when a trial tests many possible modifiers. Dana-Farber researchers described the left-sided result as a finding that requires further investigation rather than evidence that high-dose vitamin D3 should be used in this subgroup.
The negative overall trial result remains the most reliable conclusion.
What the evidence cannot answer
SOLARIS answers a specific treatment question: whether high-dose vitamin D3 improves outcomes when added to chemotherapy and bevacizumab in previously untreated metastatic colorectal cancer. It does not establish that vitamin D is irrelevant to cancer biology, that correcting vitamin D deficiency has no health value, or that vitamin D has no role in other diseases.
The trial also cannot determine whether a narrowly defined molecular or anatomic subgroup might respond differently. Patients with known mismatch repair-deficient or microsatellite instability-high disease were excluded, and the study was not designed to prove benefit within the exploratory left-sided subgroup.
Nor should these results be generalized to cancer prevention. Large randomized prevention trials have generally not shown that vitamin D supplementation reduces overall cancer incidence, but prevention and treatment are separate clinical questions with different populations and endpoints.
The Phase 3 result changes how the earlier evidence should be read
The practical conclusion from SOLARIS is narrow but important. High-dose vitamin D3 should not be viewed as an evidence-based add-on treatment for previously untreated metastatic colorectal cancer on the strength of the earlier Phase 2 signal.
The trial also offers a useful example of why larger confirmatory studies matter. Observational associations and early randomized signals can justify a Phase 3 test, but clinical recommendations depend on whether that benefit survives rigorous confirmation.
References
- Ng K, Ou FS, 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.
- Ng K, Nimeiri HS, McCleary NJ, et al. Effect of High-Dose vs Standard-Dose Vitamin D3 Supplementation on Progression-Free Survival Among Patients With Advanced or Metastatic Colorectal Cancer: The SUNSHINE Randomized Clinical Trial. JAMA. 2019;321(14):1370-1379. DOI: 10.1001/jama.2019.2402.
- National Cancer Institute. Vitamin D3 with Chemotherapy and Bevacizumab in Treating Patients with Advanced or Metastatic Colorectal Cancer, SOLARIS Trial. NCI trial record.
- Dana-Farber Cancer Institute. High-Dose vitamin D3 does not provide benefit for metastatic colorectal cancer. September 15, 2024. Dana-Farber research summary.