RO7656594 for Prostate Cancer

Recruiting at 34 trial locations

Overseen By GO44537 https://forpatients.roche.com/

Age: 18+

Sex: Male

Trial Phase: Phase 1

Sponsor: Genentech, Inc.

Must be taking: AR-targeted therapy

Must not be taking: AR protein degrader

Disqualifiers: CNS metastases, Leptomeningeal disease, others

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

Compensation: Varies

Number of Visits: Unknown

160 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a new drug called RO7656594 to see if it is safe and effective for people with advanced prostate cancer. The study focuses on patients whose cancer has spread and may not respond to current treatments. Researchers are looking at how the drug moves through the body and its impact on cancer cells to find the best dose and schedule for future studies.

Will I have to stop taking my current medications?

The trial requires that you stop taking any approved systemic anti-cancer therapy at least 14 days before starting the study treatment. If you're on an investigational agent, you need to stop it 28 days before. Other medications are not specifically mentioned, so it's best to discuss with the trial team.

What data supports the effectiveness of the drug RO7656594 for prostate cancer?

Research shows that targeting RORγ, which is involved in prostate cancer, can reduce tumor growth by blocking androgen receptor activity. This suggests that drugs like RO7656594, which may work similarly, could be effective in treating prostate cancer. ^{1 2 3 4 5}

What is known about the safety of RO7656594 for prostate cancer treatment?

The research does not provide specific safety data for RO7656594, but similar treatments for prostate cancer, like novel oral anti-androgens, have been associated with increased fatigue and decreased risk of anemia. Patients should be monitored for these side effects. ^{1 4 6 7 8}

What makes the drug RO7656594 unique for treating prostate cancer?

RO7656594 targets RORγ, a protein that drives androgen receptor (AR) hyperactivity in castration-resistant prostate cancer (CRPC). By blocking RORγ, this drug suppresses AR signaling and tumor growth, offering a novel approach compared to traditional therapies like androgen deprivation therapy, which often face resistance. ^{1 6 9 10 11}

Research Team

Clinical Trials

Principal Investigator

Genentech, Inc.

Eligibility Criteria

This trial is for men with advanced or metastatic prostate cancer who have already tried at least one second-generation hormone therapy and a taxane chemotherapy, unless they can't tolerate or refused the chemo. They should be relatively active and able to care for themselves (ECOG ≤1).

Inclusion Criteria

I am fully active and can carry on all pre-disease activities without restriction.

My prostate cancer has spread and is not small-cell or neuroendocrine type.

I have been treated with a specific prostate cancer medication before.

Exclusion Criteria

I have brain metastases or leptomeningeal disease that hasn't been treated.

I haven't had cancer treatment in the last 14 days or within the drug's elimination period.

Treatment with any investigational agent within 28 days prior to the first study treatment

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive RO7656594 at increasing doses in 28-day cycles until a threshold is reached

Varies per cohort

Multiple visits per cycle

Expansion

Participants receive RO7656594 at or below the maximum tolerated dose

Up to 12 months

Multiple visits per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• RO7656594

Trial Overview The study is testing RO7656594's safety, how it affects the body, and its effectiveness in treating prostate cancer. Participants will receive different doses of RO7656594 to find out what amount works best for future studies.

Participant Groups

Group I: Stage 2: Expansion Experimental Treatment 1 Intervention

Participants will receive RO7656594 at or below the maximum tolerated dose (MTD) or maximum administered dose (MAD).

Group II: Stage 1: Dose Escalation Experimental Treatment 1 Intervention

Participants will receive RO7656594 administered at a specified dose on specific days in each 28-day cycle. The dose will be increased in successive cohorts until a study-specific threshold is reached.

Who Is Running the Clinical Trial?

Genentech, Inc.

Lead Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Findings from Research

RORγ is identified as a promising therapeutic target in castration-resistant prostate cancer, as it is found to promote hyperactivity of the androgen receptor (AR) in this disease.

Using small-molecule antagonists to block RORγ effectively suppresses AR activity and slows tumor growth in mouse models, including those resistant to the antiandrogen enzalutamide.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Therapeutic Target for Prostate Cancer. [2017]

In the SPARTAN study involving 1207 patients with nonmetastatic castration-resistant prostate cancer, apalutamide significantly improved health-related quality of life (HRQoL) compared to placebo, with patients maintaining better scores over time.

Patients receiving apalutamide experienced minimal side effects and reported no worsening of fatigue, while those on placebo showed a decline in quality of life after about one year, highlighting the efficacy and tolerability of apalutamide in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-related Quality of Life at the SPARTAN Final Analysis of Apalutamide for Nonmetastatic Castration-resistant Prostate Cancer Patients Receiving Androgen Deprivation Therapy. Oudard, S., Hadaschik, B., Saad, F., et al.[2022]

In the SPARTAN study, apalutamide combined with androgen deprivation therapy (ADT) led to rapid and significant reductions in prostate-specific antigen (PSA) levels in most patients, with 90% achieving at least a 50% reduction by 6 months, compared to only 1.5% in the placebo group.

Deep PSA responses (≥90% reduction or PSA ≤0.2 ng/ml) at 6 months were strongly linked to improved outcomes, including metastasis-free survival and overall survival, indicating that early PSA monitoring can be a valuable prognostic tool for patients with high-risk nonmetastatic castration-resistant prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Deep Prostate-specific Antigen Response following Addition of Apalutamide to Ongoing Androgen Deprivation Therapy and Long-term Clinical Benefit in SPARTAN. Saad, F., Small, EJ., Feng, FY., et al.[2022]

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, 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]

RORγ antagonists, such as XY018 and compound 31, effectively inhibit tumor growth in metastatic castration-resistant prostate cancer (mCRPC) models, including patient-derived xenografts, suggesting a new therapeutic avenue.

The study identifies a novel mechanism where RORγ and PBK interact to enhance androgen receptor signaling, and their dual inhibition shows synergistic effects in reducing cancer cell growth, highlighting a promising strategy for treating advanced prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting Feedforward Loops Formed by Nuclear Receptor RORγ and Kinase PBK in mCRPC with Hyperactive AR Signaling. Zhang, X., Huang, Z., Wang, J., et al.[2022]

The compound XY101, a RORγ inverse agonist, showed strong anti-prostate cancer activity with an IC50 value of 30 nM and effectively inhibited tumor growth in a mouse model.

XY101 demonstrated good oral bioavailability (59%) and a half-life of 7.3 hours, indicating its potential as a convenient and effective treatment option for prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discovery and Characterization of XY101, a Potent, Selective, and Orally Bioavailable RORγ Inverse Agonist for Treatment of Castration-Resistant Prostate Cancer. Zhang, Y., Wu, X., Xue, X., et al.[2020]

A meta-analysis of 15 randomized controlled trials involving 16,795 patients found that novel oral anti-androgens (NOAAs) are associated with a 26% increased risk of all-grade fatigue compared to standard treatments.

Interestingly, NOAAs were linked to a decreased risk of anemia, suggesting that while they may cause fatigue, they do not significantly increase the likelihood of anemia in patients undergoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk of Fatigue and Anemia in Patients With Prostate Cancer Treated With Novel Oral Anti-androgens: A Meta-Analysis of Randomized Controlled Trials. Babkoor, AA., Aljabri, Y., Alzubaidi, A., et al.[2022]

ROR2 expression is significantly lower in metastatic prostate cancer (PCa) compared to primary tumors, and low levels of ROR2 are associated with poorer survival and higher recurrence rates in patients.

Increasing ROR2 levels in PCa cells inhibits their migration and invasion by regulating the PIAS3-PI3K-AKT2 signaling pathway, suggesting that ROR2 could be a potential therapeutic target to prevent PCa metastasis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ROR2 suppresses metastasis of prostate cancer via regulation of miR-199a-5p-PIAS3-AKT2 signaling axis. Tseng, JC., Huang, SH., Lin, CY., et al.[2021]

The study identifies a novel mechanism by which the RON receptor in prostate cancer cells promotes castration-resistant prostate cancer (CRPC) through the recruitment of tumor-associated macrophages, which enhance cancer cell signaling.

Targeting both RON and macrophages in a mouse model showed potential to sensitize CRPC to androgen deprivation therapy (ADT), suggesting that combining macrophage-targeting agents with RON/Axl inhibition could improve treatment outcomes for patients with CRPC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prostate tumor RON receptor signaling mediates macrophage recruitment to drive androgen deprivation therapy resistance through Gas6-mediated Axl and RON signaling. Brown, NE., Jones, A., Hunt, BG., et al.[2023]

ROR-γ is overexpressed in metastatic castration-resistant prostate cancer (CRPC) and drives the expression of the androgen receptor (AR), which is crucial for tumor growth.

Using ROR-γ antagonists not only reduces AR expression and its variant AR-V7 but also suppresses tumor growth in AR-expressing models and enhances the effectiveness of enzalutamide, showing potential as a new treatment strategy for advanced prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer. Wang, J., Zou, JX., Xue, X., et al.[2023]

References

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

New Therapeutic Target for Prostate Cancer. [2017]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Health-related Quality of Life at the SPARTAN Final Analysis of Apalutamide for Nonmetastatic Castration-resistant Prostate Cancer Patients Receiving Androgen Deprivation Therapy. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Deep Prostate-specific Antigen Response following Addition of Apalutamide to Ongoing Androgen Deprivation Therapy and Long-term Clinical Benefit in SPARTAN. [2022]

4. 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]

5. 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]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Targeting Feedforward Loops Formed by Nuclear Receptor RORγ and Kinase PBK in mCRPC with Hyperactive AR Signaling. [2022]

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

Discovery and Characterization of XY101, a Potent, Selective, and Orally Bioavailable RORγ Inverse Agonist for Treatment of Castration-Resistant Prostate Cancer. [2020]

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

Risk of Fatigue and Anemia in Patients With Prostate Cancer Treated With Novel Oral Anti-androgens: A Meta-Analysis of Randomized Controlled Trials. [2022]

9. England pubmed.ncbi.nlm.nih.gov

ROR2 suppresses metastasis of prostate cancer via regulation of miR-199a-5p-PIAS3-AKT2 signaling axis. [2021]

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

Prostate tumor RON receptor signaling mediates macrophage recruitment to drive androgen deprivation therapy resistance through Gas6-mediated Axl and RON signaling. [2023]

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

ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer. [2023]