High-Dose Vitamin D Disappoints in Metastatic CRC: SOLARIS

BARCELONA, Spain — The addition of high-dose vitamin D supplementation to standard chemotherapy plus bevacizumab did not result in a significant progression-free survival benefit in patients with metastatic colorectal cancer (CRC) in the SOLARIS study.

The researchers did identify a small progression-free survival improvement in patients with left-sided primary tumors, but this should be considered “hypothesis-generating,” according to lead investigator Kimmie Ng, MD, MPH, with Dana-Farber Cancer Institute, Boston.

Ng reported results from the first phase 3 randomized controlled trial to test high-dose vitamin D in metastatic CRC at the European Society for Medical Oncology (ESMO) Annual Meeting 2024.

Vitamin D has demonstrated anticancer properties, including inhibiting tumor growth and inducing cell death, in preclinical studies, and the phase 2 SUNSHINE trial found higher vitamin D levels improved progression-free survival in patients with advanced or metastatic CRC.

The phase 3 SOLARIS trial aimed to confirm these findings.

The trial enrolled 455 patients with previously untreated, locally advanced or metastatic CRC. Patients had measurable disease and good performance status and had not been taking regular high-dose vitamin D over the past year. Patients had no preexisting hypercalcemia or any condition predisposing to hypercalcemia.

Participants were randomized to standard chemotherapy with FOLFOX or FOLFIRI plus bevacizumab with either high-dose vitamin D3 (a loading dose of 8000 IU/d for 2 weeks, followed by a maintenance dose of 4000 IU/d) or to a control receiving 400-IU/d vitamin D3 (standard-dose group).

The two groups were well balanced, with no significant differences in demographics, tumor or treatment factors, or genomic alterations.

After a median follow-up of 20 months, Ng and colleagues observed no statistically significant difference in progression-free survival between the two groups — a median of 11.8 months in the high-dose vitamin D group vs 10.3 months in the standard-dose group (hazard ratio [HR], 0.92; P = .25).

The researchers also reported no significant difference between the two groups in overall survival outcomes — a median of 25.6 months for the high-dose group vs 27.0 months for the standard-dose group (HR, 1.05; P = .34) — or in objective response rate — 51% for the high-dose group vs 44% for the standard-dose group (P = .12).

Subgroup analysis suggested a potential benefit for patients with left-sided primary tumors, where high-dose vitamin D was associated with a small but significant improvement in progression-free survival (HR, 0.74; interaction P = .015).

This apparent benefit in patients with left-sided tumors required further study and confirmation, Ng said. However, “we should not jump into another clinical trial of vitamin D for left-sided patients until we better understand whether there’s a biological explanation for it.”

Ng noted that there is preliminary data from a separate study that suggested a possible higher expression of the vitamin D receptors in left-sided tumors than in right-sided tumors.

The researchers also found no significant differences in grade 3 or higher adverse events between the two treatment groups, and compliance with vitamin D supplementation was high in both groups.

In response to an audience question, Ng noted that baseline vitamin D levels were unknown in SOLARIS and in SUNSHINE.

“We know that almost all patients with metastatic colorectal cancer have baseline vitamin D deficiency, and we excluded those who likely were very sufficient based on prior high-dose vitamin D use in the year before study enrollment,” she explained.

Given the positive results from SUNSHINE, SOLARIS was a “very good idea and it was well done,” said the study discussant, Michel Ducreux, MD, PhD, with Gustave Roussy Cancer Center, Paris-Saclay University in France.

Unfortunately, it’s a completely negative trial, which is disappointing but also important, said Ducreux, who also did not think a new trial in left-sided tumors would be worthwhile.

Funding for SOLARIS was provided in part by the National Cancer Institute, the Alliance for Clinical Trials in Oncology, and the Dana-Farber Cancer Institute. Ng had disclosed advisory board, consulting, or speaker activities for AbbVie, Bayer, CytomX, Etiome, GlaxoSmithKline, Jazz Pharmaceuticals, Pfizer, Revolution Medicines, and Seagen; expert testimony for CRICO; and serves as an associate editor of JAMA. Ducreux had disclosed various relationships with Roche, Merck Serono, Ipsen, Amgen, Bayer, Servier, Pierre Fabre, Incyte, and other entities.