Opevesostat-Based Treatments for Prostate Cancer

Recruiting at 75 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Merck Sharp & Dohme LLC

Must be taking: Bone resorptive therapy

Must not be taking: Systemic steroids, Immunosuppressants

Disqualifiers: Diabetes, Cardiovascular disease, Pneumonitis, others

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

Compensation: Varies

Number of Visits: Unknown

220 Participants Needed

Trial Summary

What is the purpose of this trial?

Substudy 01A is part of a larger research study that is testing experimental treatments for metastatic castration-resistant prostate cancer (mCRPC). The larger study is the umbrella study (U01). The goal of substudy 01A is to evaluate the safety and efficacy of opevesostat-based treatment combinations, or as a single agent, in participants with mCRPC. This substudy will have two phases: a safety lead-in phase and an efficacy phase. The safety lead-in phase will be used to evaluate the safety and tolerability, and to establish a recommended Phase 2 dose (RP2D) for the opevesostat-based treatment combinations. There will be no hypothesis testing in this study.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you must have stable doses of bone resorptive therapy for more than 4 weeks before joining, and you cannot have received systemic anticancer therapy within 4 weeks before starting the trial.

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

Research shows that ODM-201, a component of the treatment, has demonstrated antitumor activity and safety in patients with metastatic castration-resistant prostate cancer, suggesting potential effectiveness in similar conditions. ^{1 2 3 4 5}

Is Opevesostat safe for humans?

ODM-201, another name for Opevesostat, has been tested in patients with prostate cancer and showed acceptable safety in early trials, meaning it was generally well-tolerated by patients. ^{1 3 5 6 7}

What makes the drug Opevesostat unique for treating prostate cancer?

Opevesostat is unique because it targets specific pathways involved in prostate cancer progression, potentially offering a new approach compared to existing treatments like chemotherapy and hormone therapies. This drug may provide an alternative for patients with hormone-refractory prostate cancer, where current options have limited effectiveness. ^{4 8 9 10 11}

Research Team

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Eligibility Criteria

This trial is for men with advanced prostate cancer that has spread and resisted hormone therapy. They should have tried up to two new hormonal treatments, be past certain previous treatments by specific times, and show current metastatic disease. Stable on bone treatment for over 4 weeks, recovered from prior therapy side effects to mild levels or normal, and if they have Hepatitis B or C or HIV, these must be well-managed.

Inclusion Criteria

My prostate cancer is confirmed without being a small cell type.

I have been on a stable dose of medication for bone health for more than 4 weeks.

I had Hepatitis C but my viral load is now undetectable.

Exclusion Criteria

I have had issues with my pituitary gland.

My diabetes is not well-managed.

I haven't had any live vaccines in the last 30 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Lead-in

Evaluate the safety and tolerability, and establish a recommended Phase 2 dose (RP2D) for the opevesostat-based treatment combinations

4 weeks

Efficacy

Evaluate the efficacy of opevesostat-based treatment combinations or as a single agent in participants with mCRPC

Up to approximately 46 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Opevesostat

Trial Overview The study tests Opevesostat alone or combined with other drugs (Docetaxel, Dexamethasone, Fludrocortisone acetate, Olaparib, Prednisone, Cabazitaxel) in treating metastatic castration-resistant prostate cancer. It includes a safety phase to find the right dose followed by an efficacy phase without hypothesis testing.

Participant Groups

Group I: Arm A4: Cabazitaxel + Opevesostat Experimental Treatment 5 Interventions

Participants receive 5 mg of opevesostat BID via oral tablet plus dexamethasone 1.5 mg by oral tablets QD and 0.1 mg fludrocortisone acetate by oral tablet QD, PLUS 20 mg/m\^2 of cabazitaxel Q3W via IV infusion, plus prednisone per approved product label BID by oral tablets until progressive disease or discontinuation.

Group II: Arm A3: Docetaxel + Opevesostat Experimental Treatment 5 Interventions

Participants receive 5 mg of opevesostat BID via oral tablet plus dexamethasone 1.5 mg by oral tablets QD and 0.1 mg fludrocortisone acetate by oral tablet QD, PLUS 75 mg/m\^2 of docetaxel once every 3 weeks (Q3W) via IV infusion, plus prednisone per approved product label BID by oral tablets until progressive disease or discontinuation.

Group III: Arm A2: Olaparib + Opevesostat Experimental Treatment 4 Interventions

Participants receive 5 mg of opevesostat BID via oral tablet plus dexamethasone 1.5 mg by oral tablets QD and 0.1 mg fludrocortisone acetate by oral tablet QD, PLUS 300 mg of olaparib BID via oral tablet until progressive disease or discontinuation.

Group IV: Arm A1: Opevesostat Experimental Treatment 3 Interventions

Participants receive 5 mg of opevesostat twice daily (BID) via oral tablet plus dexamethasone 1.5 mg by oral tablets once daily (QD) and 0.1 mg fludrocortisone acetate by oral tablet QD until progression or discontinuation.

Who Is Running the Clinical Trial?

Merck Sharp & Dohme LLC

Lead Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Orion Corporation, Orion Pharma

Industry Sponsor

Trials

140

Recruited

45,200+

Liisa Hurme

Orion Corporation, Orion Pharma

Chief Executive Officer since 2022

PhD in Biochemistry, University of Helsinki

Hilpi Rautelin

Orion Corporation, Orion Pharma

Chief Medical Officer since 2023

MD, University of Turku

Findings from Research

ODM-201, a second-generation androgen receptor inhibitor, demonstrated similar pharmacokinetics between its tablet and capsule formulations, indicating that the tablet can be effectively used in treatment.

In a trial with 30 chemotherapy-naive men with metastatic castration-resistant prostate cancer, 83% showed a significant PSA response (≥50% reduction), and the treatment was well tolerated, with common side effects being fatigue and nausea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, Antitumor Activity, and Safety of ODM-201 in Patients with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer: An Open-label Phase 1 Study. Massard, C., Penttinen, HM., Vjaters, E., et al.[2018]

In Sweden, from 2018 to 2022, 57% of men diagnosed with de novo metastatic castration-sensitive prostate cancer and a life expectancy of over 3 years received additional treatments alongside standard androgen deprivation therapy, indicating a significant uptake of new therapies.

There was a notable 2-fold increase in the use of these treatments over the study period, primarily driven by a 6-fold rise in the use of abiraterone, enzalutamide, or apalutamide, suggesting a positive trend in adherence to treatment guidelines, though further improvements are needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Uptake of doublet therapy for de novo metastatic castration sensitive prostate cancer: a population-based drug utilisation study in Sweden. Gedeborg, R., Sandin, F., Thellenberg-Karlsson, C., et al.[2023]

In the ARADES trial involving 134 patients with castration-resistant prostate cancer (CRPC), prolonged treatment with the androgen receptor antagonist ODM-201 was well tolerated, showing a consistent safety profile with no unexpected adverse effects over an average treatment duration of 8.2 months.

Patients who had not previously undergone chemotherapy experienced significantly longer median times to PSA progression (25.2 months) and radiographic progression (14.0 months) compared to those who had been pretreated, suggesting that ODM-201 may be particularly effective in chemotherapy-naïve patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Antitumour Activity of ODM-201 (BAY-1841788) in Castration-resistant, CYP17 Inhibitor-naïve Prostate Cancer: Results from Extended Follow-up of the ARADES Trial. Fizazi, K., Massard, C., Bono, P., et al.[2019]

New hormonal therapies like abiraterone and enzalutamide have significantly changed the treatment landscape for metastatic castration-resistant prostate cancer, offering new options for patients.

With multiple new treatments in trials targeting various pathways, there is an urgent need to identify predictive markers to guide treatment sequencing and optimize patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[New therapies in metastatic castration resistant prostate cancer]. Thibault, C., Massard, C.[2015]

Extended treatment with ODM-201, an androgen receptor antagonist, was well tolerated in 41 chemotherapy-naïve and CYP17 inhibitor-naïve patients with metastatic castration-resistant prostate cancer (mCRPC), showing an overall adverse event incidence of 80.5%, mostly mild (grade 1-2).

The treatment demonstrated sustained antitumour activity, with median times to prostate-specific antigen (PSA) progression of 12.4 months and radiological progression of 15.3 months, indicating that ODM-201 could be a viable long-term therapeutic option for mCRPC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Antitumour Activity of ODM-201 (BAY-1841788) in Chemotherapy-naïve and CYP17 Inhibitor-naïve Patients: Follow-up from the ARADES and ARAFOR Trials. Shore, ND., Tammela, TL., Massard, C., et al.[2019]

ODM-201, an androgen receptor inhibitor, was found to be safe and well-tolerated in men with metastatic castration-resistant prostate cancer, with no dose-limiting toxic effects reported during the trial involving 24 patients in phase 1.

At 12 weeks, 29% to 33% of patients across different dosage groups (200 mg, 400 mg, and 1400 mg) showed a significant PSA response, indicating that ODM-201 effectively suppresses disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity and safety of ODM-201 in patients with progressive metastatic castration-resistant prostate cancer (ARADES): an open-label phase 1 dose-escalation and randomised phase 2 dose expansion trial. Fizazi, K., Massard, C., Bono, P., et al.[2017]

Apalutamide, enzalutamide, and darolutamide have significantly changed the treatment options for patients with nonmetastatic castration-resistant prostate cancer, highlighting the importance of selecting the right treatment based on efficacy and safety.

Safety considerations are crucial when choosing among these second-generation androgen receptor inhibitors, as they can affect not only immediate side effects but also long-term healthcare outcomes and patient preferences.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety differences across androgen receptor inhibitors in nonmetastatic castration-resistant prostate cancer. Shore, N., Garcia-Horton, V., Terasawa, E., et al.[2023]

Docetaxel-based chemotherapy has been shown to provide a survival benefit for men with metastatic, hormone-refractory prostate cancer, marking a significant advancement in treatment since 2004.

Current research is exploring various new therapeutic targets and treatment options, including antiangiogenic therapies and immunomodulatory agents, highlighting the need for a multidisciplinary approach to improve patient outcomes and quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current standard and investigational approaches to the management of hormone-refractory prostate cancer. Mendiratta, P., Armstrong, AJ., George, DJ.[2020]

In a study involving mice with prostate cancer, treatment with chemotherapy and anti-androgen drugs increased the presence of TROP2high cells, which are believed to be tumor-initiating cells (TICs) that contribute to treatment resistance.

High levels of TROP2 expression in prostate cancer patients, especially those with early-stage tumors, may indicate a poorer prognosis and could serve as a predictive biomarker for treatment response in androgen-sensitive prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High expression of TROP2 characterizes different cell subpopulations in androgen-sensitive and androgen-independent prostate cancer cells. Xie, J., Mølck, C., Paquet-Fifield, S., et al.[2018]

Prostate cancer is a significant health issue, being the most common cancer among men in the U.S. and the second leading cause of cancer death, with limited treatment options leading to a median survival of only 1-2 years for metastatic castrate-resistant cases.

Recent developments in therapies for metastatic hormone-refractory prostate cancer have shown mixed results, with some promising agents like abiraterone and Provenge still holding potential, while circulating tumor cells are expected to play a crucial role in future treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging therapies in castrate-resistant prostate cancer. Lassi, K., Dawson, NA.[2014]

Recent advancements in prostate cancer treatment include new drugs like abiraterone acetate and enzalutamide, which effectively target androgen receptor signaling and have shown significant benefits when combined with androgen deprivation therapy (ADT) for advanced stages of the disease.

Ongoing clinical trials are exploring various innovative therapies, including second-generation AR antagonists and targeted treatments based on molecular profiling, which aim to personalize and improve treatment outcomes for prostate cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent Advances in Prostate Cancer Treatment and Drug Discovery. Nevedomskaya, E., Baumgart, SJ., Haendler, B.[2022]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, Antitumor Activity, and Safety of ODM-201 in Patients with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer: An Open-label Phase 1 Study. [2018]

2. Sweden pubmed.ncbi.nlm.nih.gov

Uptake of doublet therapy for de novo metastatic castration sensitive prostate cancer: a population-based drug utilisation study in Sweden. [2023]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Safety and Antitumour Activity of ODM-201 (BAY-1841788) in Castration-resistant, CYP17 Inhibitor-naïve Prostate Cancer: Results from Extended Follow-up of the ARADES Trial. [2019]

4. France pubmed.ncbi.nlm.nih.gov

[New therapies in metastatic castration resistant prostate cancer]. [2015]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Safety and Antitumour Activity of ODM-201 (BAY-1841788) in Chemotherapy-naïve and CYP17 Inhibitor-naïve Patients: Follow-up from the ARADES and ARAFOR Trials. [2019]

6. England pubmed.ncbi.nlm.nih.gov

Activity and safety of ODM-201 in patients with progressive metastatic castration-resistant prostate cancer (ARADES): an open-label phase 1 dose-escalation and randomised phase 2 dose expansion trial. [2017]

7. England pubmed.ncbi.nlm.nih.gov

Safety differences across androgen receptor inhibitors in nonmetastatic castration-resistant prostate cancer. [2023]

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

Current standard and investigational approaches to the management of hormone-refractory prostate cancer. [2020]

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

High expression of TROP2 characterizes different cell subpopulations in androgen-sensitive and androgen-independent prostate cancer cells. [2018]

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

Emerging therapies in castrate-resistant prostate cancer. [2014]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Recent Advances in Prostate Cancer Treatment and Drug Discovery. [2022]