Vytorin for Prostate Cancer

Overseen By Amy Hoang

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: Cedars-Sinai Medical Center

Must be taking: Statins, Ezetimibe

Must not be taking: CYP3A4 inhibitors, Gemfibrozil

Disqualifiers: Liver failure, Severe myalgia, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 3-6 months

140 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot participate if you are using certain medications that interact with statins or ezetimibe. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

What data supports the effectiveness of the drug Vytorin for prostate cancer?

Research suggests that statins, like simvastatin (a component of Vytorin), may improve survival in advanced prostate cancer, especially when used with other treatments like androgen deprivation therapy. Additionally, simvastatin has shown potential in enhancing the effects of other cancer treatments in prostate cancer models. ^{1 2 3 4 5}

Is Vytorin (Ezetimibe/Simvastatin) safe for use in humans?

Vytorin, which combines ezetimibe and simvastatin, is generally considered safe for humans as it is FDA-approved for lowering cholesterol. Studies have shown it may also help slow prostate cancer growth by reducing cholesterol levels, but its safety profile is primarily based on its use for cholesterol management. ^{1 3 4 6 7}

How does the drug Vytorin differ from other treatments for prostate cancer?

Vytorin, a combination of ezetimibe and simvastatin, is unique because it targets cholesterol levels, which may help slow prostate cancer growth by reducing tumor blood vessel formation (angiogenesis) and modifying lipid profiles associated with poor outcomes. This approach is different from standard prostate cancer treatments that typically focus on hormone levels or chemotherapy. ^{1 4 5 6 8}

What is the purpose of this trial?

To test the hypothesis that intensive cholesterol lowering (iCL) therapy has anti-tumor immune modulating activity, the investigators will conduct an open-label, single-arm phase II trial in prostate cancer patients who are in active surveillance and undergoing a planned surveillance biopsy in 3-6 months. Eligible patients will initiate iCL with Vytorin®(group 1, 2, and 3), an FDA-approved combination of ezetimibe and simvastatin used to lower atherogenic low density lipoprotein cholesterol (LDL-C) or Ezetimibe (group 4). Starting dose will be determined by current statin use and LDL-C levels. Dose modifications of VYTORIN will be employed with the goal of achieving LDL-C \<70 mg/dl. Dose adjustment is not allowed for ezetimibe.

Research Team

Hyung L. Kim

Principal Investigator

Cedars-Sinai Medical Center

Eligibility Criteria

This trial is for men over 50 with prostate cancer who are being closely monitored (active surveillance) and have a planned biopsy in the next 3-6 months. Participants should be willing to follow study procedures, may have conditions like hypertension, high cholesterol, diabetes, or a family history of heart disease, and could be current/former smokers with BMI >25.

Inclusion Criteria

Provision of signed and dated informed consent form

Stated willingness to comply with all study procedures and availability for the duration of the study

I can take pills and will follow a daily medication routine.

Exclusion Criteria

History of allergic or severe reaction to either study agent

I have severe liver problems.

I am currently taking the highest dose of VYTORIN.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive intensive cholesterol-lowering therapy with Vytorin or Ezetimibe

3-6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Intensive Cholesterol-Lowering Therapy

Trial Overview The trial is testing Vytorin®, a combination of ezetimibe and simvastatin that lowers 'bad' LDL cholesterol. It's believed this intensive cholesterol-lowering might help the immune system fight cancer. Patients will start on doses based on their current statin use and LDL levels, aiming to get LDL under 70 mg/dl.

Participant Groups

Group I: Intensive Lipid Lowering Experimental Treatment 2 Interventions

Single arm with dual agents (ezetimibe and simvastatin) or single agent (ezetimibe). These agents target the two primary sources of cholesterol, absorption in the gut (ezetimibe) and synthesis in the liver (simvastatin). The dual agents are available in a single pill that is FDA approved and sold under the trade name, Vytorin.

Intensive Cholesterol-Lowering Therapy is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Vytorin for:

• Hyperlipidemia
• Homozygous familial hypercholesterolemia

Approved in European Union as Inegy for:

• Hyperlipidemia
• Homozygous familial hypercholesterolemia

Approved in Canada as Vytorin for:

• Hyperlipidemia
• Homozygous familial hypercholesterolemia

Who Is Running the Clinical Trial?

Cedars-Sinai Medical Center

Lead Sponsor

Trials

523

Recruited

165,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study involving 90 male nude mice with prostate cancer, the combination of simvastatin and ezetimibe actually accelerated tumor growth, suggesting that these cholesterol-lowering drugs may not be effective in slowing prostate cancer progression.

Ezetimibe reduced serum cholesterol levels by 15%, but paradoxically led to higher cholesterol levels in tumors, indicating that prostate tumors may adapt by increasing low-density lipoprotein receptors, which could be a mechanism of resistance against cholesterol-lowering therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evidence for Feedback Regulation Following Cholesterol Lowering Therapy in a Prostate Cancer Xenograft Model. Masko, EM., Alfaqih, MA., Solomon, KR., et al.[2020]

In a meta-analysis of 25 studies involving 119,878 men with advanced prostate cancer, concurrent statin use was linked to a 27% reduction in overall mortality and a 35% reduction in prostate cancer-specific mortality, suggesting a potential survival benefit for patients undergoing androgen deprivation therapy (ADT) or androgen receptor axis-targeted therapies (ARATs).

The analysis indicated that statins may provide a greater survival advantage for men receiving ARATs compared to those on ADT alone, with a hazard ratio of 0.40 for prostate cancer-specific mortality in the ARAT group, highlighting the need for further randomized clinical trials to confirm these observational findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Statin Use and Survival Among Men Receiving Androgen-Ablative Therapies for Advanced Prostate Cancer: A Systematic Review and Meta-analysis. Jayalath, VH., Clark, R., Lajkosz, K., et al.[2022]

Statin use in advanced prostate cancer patients undergoing androgen deprivation therapy (ADT) was associated with a significant reduction in all-cause mortality (HR = 0.73) and cancer-specific mortality (HR = 0.64), based on a systematic review of nine studies involving over 100,000 patients.

While statins showed promising benefits for patients treated with ADT, the evidence for their efficacy in those with metastatic castration-resistant prostate cancer (mCRPC) receiving abiraterone or enzalutamide was inconclusive, highlighting the need for further randomized controlled trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of statins on advanced prostate cancer patients with androgen deprivation therapy or abiraterone/enzalutamide: A systematic review and meta-analysis. Yang, H., Pang, L., Hu, X., et al.[2021]

The combination of valproic acid and simvastatin shows a synergistic antitumor effect against metastatic castration-resistant prostate cancer (mCRPC) by targeting cancer stem cells and inhibiting the YAP oncogene, which is linked to treatment resistance.

This drug combination not only enhances the effectiveness of docetaxel, a standard treatment for mCRPC, but also helps overcome docetaxel resistance, suggesting a promising new strategy for managing this challenging disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synergistic antitumor interaction of valproic acid and simvastatin sensitizes prostate cancer to docetaxel by targeting CSCs compartment via YAP inhibition. Iannelli, F., Roca, MS., Lombardi, R., et al.[2021]

In a study of 87,346 men with advanced prostate cancer undergoing androgen deprivation therapy, those who used statins for at least 6 months had significantly improved overall survival (6.5 years vs. 4.0 years) and cancer-specific survival (94.0% vs. 87.3%) compared to non-users.

Statin use was also linked to a longer time before experiencing skeletal-related events, suggesting that these medications could be beneficial adjuncts to standard cancer treatment, although further research is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The impact of statins in combination with androgen deprivation therapyin patients with advanced prostate cancer: A large observational study. Anderson-Carter, I., Posielski, N., Liou, JI., et al.[2020]

In a study using ezetimibe, a cholesterol-blocking drug, researchers found that high cholesterol levels promote the growth of prostate cancer tumors in mice, while lowering cholesterol levels slows tumor growth.

The study also revealed that reducing cholesterol levels decreases tumor blood vessel formation, suggesting that managing cholesterol could be a potential strategy to inhibit prostate cancer progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ezetimibe is an inhibitor of tumor angiogenesis. Solomon, KR., Pelton, K., Boucher, K., et al.[2021]

In a study of 6,518 men followed from 1990 to 2012, long-term use of lipid-lowering medications, particularly statins, was associated with a significantly lower risk of developing prostate cancer (HR = 0.68).

Current users of lipid-lowering medications showed a potential reduction in the risk of dying from prostate cancer, suggesting a protective effect, although this finding was not statistically significant (HR = 0.67).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Longer-term Lipid-lowering Drug Use and Risk of Incident and Fatal Prostate Cancer in Black and White Men in the ARIC Study. Mondul, AM., Joshu, CE., Barber, JR., et al.[2022]

In a study of 27 men with metastatic castration-resistant prostate cancer (mCRPC), adding simvastatin to standard treatment significantly improved the lipidomic profile, with 45% of men with a poor prognostic lipid signature (3LS) converting to a more favorable profile after 12 weeks of treatment.

Simvastatin treatment led to a significant reduction in harmful sphingolipids in men who lost the 3LS, indicating its potential to enhance treatment outcomes in mCRPC by modifying lipid metabolism, independent of changes in cholesterol levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modulation of Plasma Lipidomic Profiles in Metastatic Castration-Resistant Prostate Cancer by Simvastatin. Mak, B., Lin, HM., Duong, T., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

Evidence for Feedback Regulation Following Cholesterol Lowering Therapy in a Prostate Cancer Xenograft Model. [2020]

2. United States pubmed.ncbi.nlm.nih.gov

Statin Use and Survival Among Men Receiving Androgen-Ablative Therapies for Advanced Prostate Cancer: A Systematic Review and Meta-analysis. [2022]

3. England pubmed.ncbi.nlm.nih.gov

The effect of statins on advanced prostate cancer patients with androgen deprivation therapy or abiraterone/enzalutamide: A systematic review and meta-analysis. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Synergistic antitumor interaction of valproic acid and simvastatin sensitizes prostate cancer to docetaxel by targeting CSCs compartment via YAP inhibition. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

The impact of statins in combination with androgen deprivation therapyin patients with advanced prostate cancer: A large observational study. [2020]

6. United States pubmed.ncbi.nlm.nih.gov

Ezetimibe is an inhibitor of tumor angiogenesis. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Longer-term Lipid-lowering Drug Use and Risk of Incident and Fatal Prostate Cancer in Black and White Men in the ARIC Study. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Modulation of Plasma Lipidomic Profiles in Metastatic Castration-Resistant Prostate Cancer by Simvastatin. [2023]