Hormone Therapy + Targeted Drugs for Prostate Cancer

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: Jonsson Comprehensive Cancer Center

Must be taking: Hormone therapy

Must not be taking: Anticoagulants, Corticosteroids, Herbal products, others

Disqualifiers: Cardiovascular disease, Seizure history, Metastases, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 6-8 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new ways to treat prostate cancer, a common and serious cancer in men. Researchers compare the effectiveness of hormone therapy alone versus hormone therapy combined with drugs that specifically target cancer cells. Participants will receive different combinations of treatments, including degarelix (a hormone therapy) and enzalutamide (a targeted drug), with some groups also receiving trametinib or dasatinib. Men with prostate cancer who are scheduled for surgery and have a PSA level over 20 or a Gleason score of 4+3 or higher might be suitable for this trial. As a Phase 2 trial, this 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 it does exclude those using certain medications like herbal products affecting prostate cancer, systemic corticosteroids above a certain dose, and medications affecting androgen levels or PSA. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that both degarelix and enzalutamide are generally well-tolerated for treating prostate cancer. Studies have found enzalutamide to be safe, though some patients experienced side effects like falls, occurring in about 12% of cases. Degarelix, when combined with enzalutamide, has been effective in many cases without major issues.

Trametinib is another drug tested in this trial as part of a new combination. Previous research on trametinib has been promising, but its safety remains under close observation.

Dasatinib, used in a different trial group, has been studied in other prostate cancer research. It shows promise, but like trametinib, more data is needed to fully understand its safety.

In this phase of the study, researchers continue to collect information on how well these drug combinations are tolerated. So far, the drugs have shown potential, but ongoing trials will provide more detailed safety information. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for prostate cancer because they offer a novel approach by combining hormone therapy with targeted drugs. The first treatment arm uses degarelix and enzalutamide, focusing solely on androgen receptor (AR) inhibition, which is a standard approach but with a potentially more effective combination. The second arm adds trametinib to the mix, introducing MEK inhibition alongside AR inhibition, which could tackle cancer cells through a different pathway and enhance treatment efficacy. Lastly, the third arm incorporates dasatinib, which brings SRC inhibition into play, potentially offering a new angle to target cancer cells more aggressively. These combinations could provide more robust control over cancer progression compared to traditional hormone therapies alone.

What evidence suggests that this trial's treatments could be effective for prostate cancer?

Research has shown that using degarelix and enzalutamide together, which participants in this trial may receive, can effectively treat prostate cancer. Real-world data indicates that this combination helps many patients manage the disease. Studies also suggest that enzalutamide may extend patients' lives when added to hormone therapies.

In this trial, some participants will receive trametinib in addition to degarelix and enzalutamide. Trametinib targets specific pathways in cancer cells, potentially enhancing treatment effectiveness. Evidence from trials shows that trametinib can improve outcomes when combined with other cancer treatments.

Another group in this trial will receive dasatinib along with degarelix and enzalutamide. Dasatinib targets different pathways in cancer cells and has shown promise in extending some patients' lives. This suggests that adding dasatinib to the treatment plan may offer additional benefits for managing prostate cancer. ^{1 2 6 7 8}

Who Is on the Research Team?

Robert Reiter, M.D.

Principal Investigator

University of California, Los Angeles

Are You a Good Fit for This Trial?

Men over 18 with advanced prostate cancer who haven't had treatment for it yet can join this trial. They should be planning to have surgery, be in good health otherwise, and have a life expectancy of at least 6 months. Key requirements include normal organ function tests, no history of heart failure or arrhythmias, and they must use contraception.

Inclusion Criteria

I am diagnosed with prostate cancer and scheduled for surgery to remove it.

Willing and able to give informed consent

Willing to abstain from procreative sex or use contraception as required

Exclusion Criteria

I am not using any experimental drugs or herbal products that affect PSA levels.

I have brain metastasis or active leptomeningeal disease.

Hospitalization within 30 days of enrollment

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive hormone therapy with or without additional drugs targeting cancer cells

6-8 weeks

Weekly visits for monitoring and drug administration

Prostatectomy

Participants undergo prostatectomy to collect tissue for analysis

2 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Dasatinib
• Degarelix
• Enzalutamide
• Trametinib

Trial Overview The study is testing if adding targeted cancer drugs (dasatinib or trametinib) to hormone therapy before surgery helps more than just hormone therapy alone. Men will get either the hormone drug degarelix plus enzalutamide or that combo with one of the other drugs.

How Is the Trial Designed?

Group I: AR inhibition only Active Control 2 Interventions

AR inhibition only Group 1: degarelix + enzalutamide Endocrine therapy with degarelix and enzalutamide will continue for a minimum of 6 weeks and a maximum of 8 weeks in all groups prior to the planned prostatectomy.

Group II: AR inhibition plus MEK inhibition Active Control 3 Interventions

AR inhibition plus MEK inhibition Group 2: trametinib + degarelix + enzalutamide In Group 2, treatment with trametinib will begin on Day 29 (i.e. four weeks after initiation of androgen deprivation). Thus, trametinib will be administered for no less than two weeks and no more than four weeks.

Group III: AR inhibition plus SRC inhibition Active Control 3 Interventions

AR inhibition plus SRC inhibition Group 3: dasatinib + degarelix + enzalutamide In Group 3, treatment with dasatinib will begin on Day 29 (i.e. four weeks after initiation of androgen deprivation). Thus, dasatinib will be administered for no less than two weeks and no more than four weeks.

Degarelix is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Firmagon for:

• Advanced hormone-dependent prostate cancer

Approved in United States as Firmagon for:

• Advanced prostate cancer

Approved in Canada as Firmagon for:

• Hormone-sensitive prostate cancer

Approved in Japan as Firmagon for:

• Prostate cancer

Who Is Running the Clinical Trial?

Jonsson Comprehensive Cancer Center

Lead Sponsor

Trials

373

Recruited

35,200+

Novartis

Industry Sponsor

Trials

1,646

Recruited

2,778,000+

Vasant Narasimhan

Novartis

Chief Executive Officer since 2018

MD from Harvard Medical School, Bachelor's in Biological Sciences from University of Chicago, Master's in Public Policy from John F. Kennedy School of Government

Shreeram Aradhye

Novartis

Chief Medical Officer since 2022

MD from Yale University, MSc in Clinical Epidemiology from University of Pennsylvania

Medivation, Inc.

Industry Sponsor

Trials

76

Recruited

11,200+

Dr. David Hung

Medivation, Inc.

Chief Executive Officer since 2003

MD from University of California, San Francisco; AB in Biology from Harvard College

Dr. Stephen M. Kelsey

Medivation, Inc.

Chief Medical Officer since 2013

MD from University of Birmingham

GlaxoSmithKline

Industry Sponsor

Trials

4,834

Recruited

8,389,000+

Headquarters

London, UK

Known For

Vaccines & Medicines

Top Products

**Advair (salmeterol, fluticasone propionate)**, **Shingrix (shingles vaccine)**, **Augmentin (amoxicillin/clavulanate potassium)**, **Ventolin (salbutamol sulfate)

Dame Emma Walmsley

GlaxoSmithKline

Chief Executive Officer since 2017

MA in Classics and Modern Languages from Oxford University

Dr. Hal Barron

GlaxoSmithKline

Chief Medical Officer since 2018

MD from Harvard Medical School

Prostate Cancer Foundation

Collaborator

Trials

52

Recruited

3,000+

Astellas Pharma Inc

Industry Sponsor

Trials

700

Recruited

236,000+

Headquarters

Tokyo, Japan

Top Products

- Xtandi (enzalutamide) for prostate cancer, - Xospata (gilteritinib) for AML, - Padcev (enfortumab vedotin) for bladder cancer, - Prograf (tacrolimus) for organ rejection prevention

Tadaaki Taniguchi

Astellas Pharma Inc

Chief Medical Officer since 2023

MD, PhD

Naoki Okamura

Astellas Pharma Inc

Chief Executive Officer since 2023

University of Tokyo, Faculty of Pharmacy

Published Research Related to This Trial

Enzalutamide significantly improved radiographic progression-free survival (rPFS) in men with chemotherapy-naïve metastatic castration-resistant prostate cancer across various disease subgroups, including nonvisceral and visceral disease, as well as low- and high-volume bone disease.

The treatment was well tolerated, showing clinically significant benefits in overall survival (OS) for most subgroups, although the results were less definitive for patients with visceral disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The PREVAIL Study: Primary Outcomes by Site and Extent of Baseline Disease for Enzalutamide-treated Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer. Evans, CP., Higano, CS., Keane, T., et al.[2022]

The ENZAMET phase III trial demonstrated that adding enzalutamide to standard treatment significantly prolongs survival in men with metastatic hormone-sensitive prostate cancer.

Enzalutamide is more effective than older nonsteroidal antiandrogen drugs, highlighting its potential as a superior treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide Bests Older NSAAs in mHSPC. [2021]

Enzalutamide (XTANDI) is an FDA-approved treatment for castration-resistant prostate cancer (CRPC) that effectively targets androgen receptor signaling, which is crucial for cancer progression.

In a Phase III clinical trial involving men with CRPC after chemotherapy, enzalutamide was well tolerated and significantly improved overall survival by 4.8 months, as indicated by reduced serum prostate-specific antigen (PSA) levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide: a novel anti-androgen with prolonged survival rate in CRPC patients. Dhingra, R., Sharma, T., Singh, S., et al.[2021]

In the ARCHES trial involving 1150 men with metastatic hormone-sensitive prostate cancer, enzalutamide combined with androgen deprivation therapy (ADT) significantly improved overall survival and radiographic progression-free survival in both men aged <75 and ≥75 years, although younger patients had better outcomes.

Despite older patients experiencing more treatment interruptions and adverse events, enzalutamide was generally well tolerated, indicating its effectiveness and safety for treating prostate cancer in older men.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Outcomes of Enzalutamide in Metastatic Hormone-sensitive Prostate Cancer in Patients Aged Gomez-Veiga, F., Szmulewitz, RZ., Holzbeierlein, J., et al.[2023]

In men with metastatic hormone-sensitive prostate cancer, enzalutamide, when combined with androgen-deprivation therapy, significantly prolonged radiographic progression-free survival compared to a placebo.

This finding highlights the efficacy of enzalutamide as an androgen-receptor inhibitor in improving outcomes for patients undergoing treatment for advanced prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eyeing Enzalutamide for Hormone-Sensitive Prostate Cancer. [2020]

Degarelix is as effective as leuprolide in suppressing testosterone levels in patients with advanced prostate cancer, with faster results and no testosterone surges, based on a 12-month phase III study.

The drug is generally well tolerated, with mild to moderate side effects, making it a viable treatment option for patients needing endocrine therapy for prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Degarelix: a review of its use in patients with prostate cancer. Carter, NJ., Keam, SJ.[2021]

A 76-year-old man developed severe thrombocytopenia after 13 days of enzalutamide treatment for castration-resistant prostate cancer, indicating that this side effect can occur early in therapy.

After discontinuing enzalutamide, the patient's platelet count recovered, and he was able to restart the medication without recurrence of thrombocytopenia; however, he later experienced a seizure, suggesting that enzalutamide may also be associated with neurological adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide-induced severe thrombocytopenia complicated by a seizure in a 76-year-old man with castration-resistant prostate cancer. Murata, M., Takizawa, I., Maruyama, R., et al.[2022]

In a study of 137 chemo-naïve patients with metastatic castration-resistant prostate cancer, Enzalutamide (EZ) showed a significantly higher PSA response rate compared to Abiraterone (AA) in the first line of treatment (95.9% vs 67%).

Both AA and EZ had comparable toxicity rates and progression-free survival (PFS) outcomes, indicating that both treatments are effective and well-tolerated options for managing mCRPC without chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Managing lines of therapy in castration-resistant prostate cancer: real-life snapshot from a multicenter cohort. Ferriero, M., Mastroianni, R., De Nunzio, C., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT01990196

NCT01990196 | Neoadjuvant Phase 2 Study Comparing ... This research will provide crucial information for the development of therapies that can improve the clinical outcome of patients with advanced prostate cancer.

2. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK571328/

Combination Treatment Options for Castration-Resistant ... A phase III clinical trial (NCT00887198) in chemotherapy-naïve CR prostate cancer patients showed a 3.7 month increase in overall survival as well as increased ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9232569/

Targeting signaling pathways in prostate cancer In this review, we summarized the targeted agents of PCa in clinical trials and their underlying mechanisms, and further discussed their limitations and future ...

4. hemonc.org hemonc.org/wiki/Prostate_cancer

Prostate cancer | HemOnc.org - A Hematology Oncology Wiki Improved Outcomes with Enzalutamide in Biochemically ... Degarelix monotherapy. Example orders. Example orders for Degarelix (Firmagon) in prostate cancer ...

5. cancer.gov cancer.gov/news-events/cancer-currents-blog/2024/fda-xtandi-prostate-cancer-psa-recurrence

Xtandi Approved for High-Risk Prostate Cancer - NCI Enzalutamide can now be used alone, or in combination with leuprolide, to treat nonmetastatic prostate cancer that is castration sensitive.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/32527692/

Five-year Survival Prediction and Safety Outcomes with ... We report a maintained long-term survival benefit with enzalutamide and risks with >5 yr of enzalutamide treatment and follow-up in men with metastatic ...

7. pfizer.com pfizer.com/news/press-release/press-release-detail/xtandir-plus-leuprolide-significantly-improves-survival

XTANDI® Plus Leuprolide Significantly Improves Survival ... XTANDI® Plus Leuprolide Significantly Improves Survival Outcomes in Men with Non-Metastatic Hormone-Sensitive Prostate Cancer with High-Risk ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT02003924

NCT02003924 | Safety and Efficacy Study of Enzalutamide ... The purpose of this study is to assess the safety and efficacy of enzalutamide in patients with non metastatic prostate cancer.