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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether lowering cholesterol levels can help the immune system fight prostate cancer. Participants will take Vytorin, a medication that combines two drugs to reduce cholesterol absorption in the gut and synthesis in the liver. Men with localized prostate cancer under active surveillance and certain cardiovascular risk factors, such as high blood pressure or diabetes, might be suitable candidates. The goal is to determine if this approach can positively affect cancer growth. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that Vytorin, a combination of ezetimibe and simvastatin, is generally safe for use. Studies have not identified a clear pattern of increased cancer risk with Vytorin. Although one study suggested a possible link to cancer, other research did not find strong evidence to support this. Ezetimibe, when used alone, also does not appear to raise cancer rates. Both treatments have FDA approval for lowering cholesterol, indicating a well-established safety record. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike standard treatments for prostate cancer, which typically focus on targeting cancer cells directly or managing hormones, this new approach uses Vytorin to lower cholesterol levels intensively. Vytorin is a combination of ezetimibe and simvastatin, which work together to block cholesterol absorption in the gut and reduce its synthesis in the liver. Researchers are excited about this treatment because recent studies suggest that cholesterol might play a role in cancer cell growth, so targeting cholesterol could offer a novel way to slow down or inhibit prostate cancer progression. By addressing cholesterol directly, this treatment could complement existing therapies, potentially enhancing overall outcomes for patients.

What evidence suggests that intensive cholesterol-lowering therapy might be an effective treatment for prostate cancer?

Research has shown that cholesterol-lowering drugs like Vytorin, which combines ezetimibe and simvastatin, might slow the progression of prostate cancer. In this trial, participants will receive intensive lipid-lowering therapy with either Vytorin's dual agents or the single agent, ezetimibe. Vytorin lowers "bad" cholesterol (LDL cholesterol) in two ways: ezetimibe reduces its absorption in the gut, and simvastatin decreases its production in the liver. Studies suggest these drugs might help prevent prostate cancer from worsening, even if they don't stop it from developing. Research involving thousands of patients has shown no increased cancer risk with Vytorin, indicating its potential safety. This suggests that significantly lowering cholesterol could help manage prostate cancer. ^{1 2 4 6 7}

Who Is on the Research Team?

Hyung L. Kim

Principal Investigator

Cedars-Sinai Medical Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

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]

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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06437574?term=Cholesterol%20AND%20fda&viewType=Table&checkSpell=&rank=8

Intensive Cholesterol-Lowering and CD8+ T Cells in ... Dose modifications of VYTORIN will be employed with the goal of achieving LDL-C <70 mg/dl. Dose adjustment is not allowed for ezetimibe. Official Title.

2. onclive.com onclive.com/view/vytorin_simvastatin_ezetimibe_trials

FDA Says Simvastatin & Ezetimibe Unlikely to Cause Cancer While analyses of interim cancer data from SHARP and IMPROVE-IT, which enrolled a cumulative 20,617 patients, found no increased risk of cancer with Vytorin, ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5822711/

Evidence for Feedback Regulation Following Cholesterol ... Epidemiologic data suggest cholesterol-lowering drugs may prevent the progression of prostate cancer, but not the incidence of the disease.

4. nejm.org nejm.org/doi/full/10.1056/NEJMsa0806603

Analyses of Cancer Data from Three Ezetimibe Trials The available results from these three trials do not provide credible evidence of any adverse effect of ezetimibe on rates of cancer.

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S000287030800656X

Vytorin Efficacy International Trial): Comparison of ... The study will recruit up to 18,000 moderate- to high-risk patients stabilized after ACS. Patients are randomized in a 1:1 ratio to once-daily doses of either ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9340271/

Ezetimibe and Cancer: Is There a Connection? - PMC Although previous studies have shown that ezetimibe combined with simvastatin increases the risk of cancer, the conclusion of SEAS trial seems ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S2666087320301708

Prospective Evaluation of Malignancy in 17708 Patients ... An increased risk of malignancy was reported with simvastatin/ezetimibe in 1,873 patients in the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) trial.