High-Dose Vitamin D3 Fails to Improve Outcomes in Metastatic Colorectal Cancer (Phase III SOLARIS Trial): JAMA | September 2026

Introduction:

Vitamin D has long attracted interest as a potential adjunctive treatment in colorectal cancer. Preclinical studies demonstrate antiproliferative, pro-differentiation, anti-inflammatory and immunomodulatory effects, while observational studies have repeatedly associated higher circulating vitamin D levels with better survival in colorectal cancer.

The randomized phase II SUNSHINE trial further strengthened this hypothesis by suggesting improved progression-free survival (PFS) with high-dose vitamin D3.

The phase III SOLARIS trial (Alliance A021703) was designed to provide the definitive test: does adding high-dose vitamin D3 to standard first-line therapy actually improve outcomes in metastatic colorectal cancer (mCRC)?

Why was this study needed?

There was a compelling biological and clinical rationale:

Colorectal cancer cells express the vitamin D receptor (VDR).

Vitamin D signaling may inhibit proliferation and angiogenesis while promoting differentiation and apoptosis.

Higher circulating 25-hydroxyvitamin D [25(OH)D] levels have been associated observationally with improved survival.

In the phase II SUNSHINE trial, high-dose vitamin D showed a promising PFS signal.

However, observational associations do not prove that supplementing vitamin D changes cancer outcomes.

A sufficiently powered phase III trial was therefore essential.

Study Design:

SOLARIS was a multicenter, double-blind, randomized phase III trial conducted through the US National Clinical Trials Network.

455 patients with previously untreated metastatic CRC were randomized to standard chemotherapy plus bevacizumab with either:

High-dose vitamin D3

8000 IU/day for 14 days

followed by 4000 IU/day

or

Standard-dose vitamin D3

400 IU/day

Systemic therapy consisted of:

mFOLFOX6 or FOLFIRI

plus bevacizumab every 2 weeks

The primary endpoint was PFS.

Did High-Dose Vitamin D Improve PFS?

No.

Median PFS was:

High-dose vitamin D3: 11.8 months

Standard dose: 10.3 months

Despite the numerical 1.5-month difference, this was not statistically significant:

P = .25

Therefore, the primary endpoint was negative.

What About Tumor Response?

There was also no statistically significant improvement in objective response rate:

High dose: 51%

Standard dose: 44%

P = .12

Again, the numerical difference did not establish therapeutic benefit.

Did High-Dose Vitamin D Improve Overall Survival?

No.

Median overall survival was:

High dose: 25.6 months

Standard dose: 27.0 months

P = .66

Importantly, there was not even a numerical OS advantage favoring high-dose supplementation.

Safety: Was High-Dose Vitamin D Harmful?

High-dose vitamin D3 was generally well tolerated.

There were no clinically meaningful differences in major grade ≥3 adverse events, including:

Neutropenia: 32% vs 30%

Hypertension: 20% vs 23%

There was also no meaningful increase in vitamin D–associated toxicities.

Thus, the trial was negative because of lack of efficacy, rather than excess toxicity.

Why Is SOLARIS Important?

The study provides an excellent example of why promising biological mechanisms, epidemiological associations and phase II signals require phase III confirmation.

The evidence evolved sequentially:

Biological plausibility

↓

Higher vitamin D levels associated with better outcomes

↓

Promising phase II SUNSHINE signal

↓

Phase III SOLARIS

↓

No significant clinical benefit

Higher vitamin D status may be associated with better prognosis without necessarily meaning that pharmacologically increasing vitamin D intake produces an antitumor effect.

This distinction between a prognostic biomarker and a therapeutic target is crucial.

What Happened to the SUNSHINE Signal?

SUNSHINE included only 139 patients and suggested improved PFS with high-dose supplementation.

SOLARIS enrolled 455 patients specifically to validate that observation.

The phase III trial failed to reproduce the benefit.

This is precisely why promising phase II findings should generally be considered hypothesis-generating until confirmed in larger trials, particularly for inexpensive, readily available interventions that can otherwise rapidly enter clinical practice without adequate evidence.

Clinical Implication:

High-dose vitamin D should not be added to chemotherapy specifically as an anticancer strategy in patients with metastatic colorectal cancer.

This does not mean that vitamin D deficiency should be ignored.

Vitamin D supplementation may remain appropriate for conventional indications such as deficiency and bone health. What SOLARIS shows is that escalating vitamin D to high doses for the purpose of improving metastatic CRC outcomes is unsupported.

Caution:

SOLARIS tested a specific clinical strategy:

High-dose vs standard-dose vitamin D3 added to first-line chemotherapy plus bevacizumab.

Therefore, the study should not be interpreted as proving that vitamin D biology has no relevance to colorectal cancer. It demonstrates that this particular supplementation strategy did not translate into improved PFS, response or OS.

Bottom Line:

The phase III SOLARIS trial closes an important clinical question: high-dose vitamin D3 added to first-line chemotherapy plus bevacizumab did not significantly improve PFS, objective response or overall survival in metastatic colorectal cancer. Despite strong biological rationale, observational associations and an encouraging phase II signal, high-dose vitamin D should not be used as an anticancer adjunct in routine mCRC treatment.