High-Dose Vitamin D3 Fails to Improve PFS in Phase 3 Metastatic CRC Trial

Adding high-dose vitamin D₃ to standard first-line chemotherapy did not significantly improve progression-free survival (PFS) in patients with previously untreated metastatic colorectal cancer (mCRC), according to results from the phase 3 SOLARIS trial (NCT04094688) published in JAMA.¹

The findings did not confirm the benefit observed in the earlier phase 2 SUNSHINE trial (NCT01516216), which suggested high-dose vitamin D₃ supplementation could delay disease progression in this population.²

Confirmatory Phase 3 Trial Tested Vitamin D₃ in mCRC

SOLARIS was a double-blind, multicenter trial conducted at 151 academic and community cancer centers across the US through the National Clinical Trials Network.¹ Between October 2019 and December 2022, investigators randomized 455 patients with previously untreated mCRC 1:1 to receive modified FOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin) or FOLFIRI (5-fluorouracil, leucovorin, irinotecan) plus bevacizumab. Patients also received either high-dose (8000 international units [IU] daily for 14 days, then 4000 IU daily) or standard-dose (400 IU daily) vitamin D₃.

The trial was designed to confirm findings from SUNSHINE, a 139-patient phase 2 study in which high-dose vitamin D₃ was associated with improved PFS (median, 13.0 vs 11.0 months) compared with standard dosing.² Those findings positioned vitamin D₃ as a promising, inexpensive adjunct to standard first-line therapy for mCRC.

High-Dose Vitamin D₃ Did Not Improve Outcomes in SOLARIS

After a median follow-up of 20 months, median PFS was 11.8 months for the high-dose group (n = 228) and 10.3 months in the standard-dose group (n = 227); the difference, however, was not statistically significant (HR, 0.92; 95% CI, 0.73-1.16; 1-sided log-rank P = .25). Objective response rates (51% vs 44%) and overall survival (median, 25.6 vs 27.0 months) were also similar between treatment arms.

A prespecified subgroup analysis identified 1 notable signal, with a significant interaction between primary tumor location and treatment effect (P = .02). Patients with left-sided tumors experienced a PFS benefit with high-dose vitamin D₃ (median, 13.8 vs 10.2 months), whereas no benefit was observed among those with right-sided tumors. The study authors noted that this finding is consistent with subgroup results from prior clinical trials and translational studies but cautioned that it remains exploratory and requires further investigation before informing treatment selection.

Regarding safety, rates of grade 3 or higher adverse events, including neutropenia and hypertension, were comparable between the groups, and vitamin D–associated toxicities such as hypercalcemia remained rare in both arms. Adherence to vitamin D₃ supplementation was high (96% in both groups), and the high-dose regimen consistently corrected vitamin D insufficiency, raising plasma 25-hydroxyvitamin D levels into the sufficient range by the first restaging scan.

Implications of the Negative SOLARIS Findings

The study authors offered several explanations for why their findings differed from those of the SUNSHINE trial. They explained that patients enrolled in SOLARIS had higher baseline vitamin D levels (median, 21.8 ng/mL) than those in SUNSHINE (median, 17.6 ng/mL); lower baseline levels have been associated with greater responses to supplementation. By chance, the high-dose group also had baseline levels that were statistically higher than those of the standard-dose group, which may have reduced the between-group difference. Additionally, vitamin D levels in the standard-dose arm increased more than expected during treatment, further narrowing the contrast between the treatment groups.

Vitamin D's relationship with CRC outcomes has long been of interest, with past mechanistic and observational studies suggesting potential anti-inflammatory and immunomodulatory benefits.³ The SOLARIS results reinforce a recurring pattern in oncology drug development in which mechanistically plausible, epidemiologically supported interventions do not always translate into confirmed benefit in phase 3 trials.¹ For payers and health systems, the findings do not support the routine use or incentivization of high-dose vitamin D₃ supplementation as an adjunct to first-line chemotherapy for unselected patients with mCRC.

Study Limitations Do Not Change the Overall Findings

The authors acknowledged several limitations, including that patients received only modified FOLFOX6 or FOLFIRI with bevacizumab, which may limit generalizability. They also noted the potential consumption of additional vitamin D supplementation outside the protocol-specified treatment. Still, the authors concluded that these limitations did not alter the trial’s overall negative findings.

“Among patients with previously untreated mCRC enrolled in a large phase 3 randomized trial, addition of high-dose vitamin D₃ vs standard dose vitamin D₃ to standard chemotherapy plus bevacizumab did not improve PFS,” they wrote.

References

1. 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. Published online August 3, 2026. doi:10.1001/jama.2026.9350
2. 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
3. Steinzor P. Vitamin D's potential role in colorectal cancer prevention, immune health. AJMC^®. April 23, 2025. Accessed August 6, 2026. https://www.ajmc.com/view/vitamin-d-s-role-in-colorectal-cancer-prevention-immune-health