Relugolix + Enzalutamide with Radiation Therapy for Prostate Cancer

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: Northwestern University

Disqualifiers: Metastatic disease, Invasive malignancy, Inflammatory bowel disease, 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: 3

Duration: 18 months

50 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, if you are on 5-alpha reductase inhibitors, you will need to stop them before starting the trial treatment.

What data supports the effectiveness of the drug Enzalutamide in combination with radiation therapy for prostate cancer?

Research shows that Enzalutamide, when added to radiation therapy, is effective in treating high-risk localized or regional nonmetastatic prostate cancer, improving overall survival and controlling prostate tumor growth. It has been shown to enhance survival in metastatic castration-resistant prostate cancer and improve outcomes when combined with salvage radiation therapy in recurrent cases. ^{1 2 3 4 5}

Is the combination of Relugolix and Enzalutamide with Radiation Therapy safe for prostate cancer treatment?

Relugolix is generally well tolerated and may have a lower risk of major heart problems compared to other treatments, but it can cause issues like prolonged QT interval (a heart rhythm problem) and embryo-fetal toxicity. Enzalutamide is widely used but can cause severe side effects like low platelet count and seizures. The combination with radiation therapy has been found to be tolerable in trials. ^{5 6 7 8 9}

What makes the drug combination of Relugolix and Enzalutamide unique for prostate cancer treatment?

The combination of Relugolix and Enzalutamide with radiation therapy is unique because Relugolix is an oral medication that rapidly suppresses testosterone without an initial surge, potentially offering improved cardiac safety compared to injectable alternatives, while Enzalutamide is a next-generation anti-androgen that enhances survival in advanced prostate cancer. ^{1 2 5 6 8}

What is the purpose of this trial?

This phase II trial tests how well relugolix and enzalutamide, in combination with radiation therapy, works in treating patients with very high risk prostate cancer. Relugolix is a form of androgen deprivation therapy. It prevents the release of testosterone, a hormone required to sustain prostate growth. Reducing testosterone levels may inhibit the proliferation of prostate tumor cells that need testosterone to grow. Enzalutamide is an androgen receptor signaling inhibitor. It inhibits the activity of prostate tumor cell receptors, which may reduce proliferation of prostate tumor cells. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Adding relugolix and enzalutamide to radiation therapy may be more effective at treating patients with very high risk prostate cancer than giving any of these treatments alone.

Research Team

Sean Sachdev

Principal Investigator

Northwestern University

Eligibility Criteria

This trial is for patients with very high risk prostate cancer. Participants should be suitable for hormone therapy and radiation, have no prior treatments for their condition, and must be able to undergo imaging tests like MRI or CT scans.

Inclusion Criteria

I have HIV with controlled viral load and specific CD4 counts.

My testosterone level was above 50 ng/dL in the last 3 months.

I use effective birth control methods.

Exclusion Criteria

I have been cancer-free for at least 2 years from a previous cancer.

My cancer has spread to other parts of my body.

I cannot take pills by mouth due to digestive issues.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive relugolix and enzalutamide orally once daily for 18 months, with image-guided radiation therapy starting after 4 months

18 months

Monthly visits for medication and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including PET/MRI and CT scans, blood sample collection, and biopsy

30 months

Every 3-6 months

Treatment Details

Interventions

• Enzalutamide
• Radiation Therapy
• Relugolix

Trial Overview The OPTIMAL trial is testing the combination of two drugs, Relugolix and Enzalutamide, with radiation therapy. The goal is to see if this combo is more effective in treating very high risk prostate cancer than standard therapies.

Participant Groups

Group I: Treatment (relugolix, enzalutamide, IGRT) Experimental Treatment 10 Interventions

Patients receive relugolix PO QD and enzalutamide PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 18 months in the absence of disease progression or unacceptable toxicity. After 4 months of treatment with relugolix and enzalutamide, patients begin IGRT per standard of care. Patients also undergo fluorine F 18 piflufolastat PET/MRI and CT on the trial, undergo collection of blood samples throughout the trial, and undergo biopsy during follow up.

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

Approved in United States as Xtandi for:

• Metastatic castration-resistant prostate cancer (mCRPC)
• Non-metastatic castration-resistant prostate cancer (nmCRPC)

Approved in European Union as Xtandi for:

• Metastatic castration-resistant prostate cancer (mCRPC)
• Non-metastatic castration-resistant prostate cancer (nmCRPC)

Approved in Canada as Xtandi for:

• Metastatic castration-resistant prostate cancer (mCRPC)
• Non-metastatic castration-resistant prostate cancer (nmCRPC)

Approved in Japan as Xtandi for:

• Metastatic castration-resistant prostate cancer (mCRPC)
• Non-metastatic castration-resistant prostate cancer (nmCRPC)

Who Is Running the Clinical Trial?

Northwestern University

Lead Sponsor

Trials

1,674

Recruited

989,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

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]

The SALV-ENZA trial is a phase II study involving adult males with recurrent prostate cancer after surgery, testing the effectiveness of combining salvage radiation therapy (SRT) with the anti-androgen enzalutamide to improve outcomes like freedom from PSA progression.

This study aims to determine if adding enzalutamide, known for its favorable side effect profile, enhances the efficacy of SRT compared to standard treatment alone, potentially leading to better clinical outcomes and paving the way for future phase III trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II randomized placebo-controlled double-blind study of salvage radiation therapy plus placebo versus SRT plus enzalutamide with high-risk PSA-recurrent prostate cancer after radical prostatectomy (SALV-ENZA). Kapoor, R., Deek, MP., McIntyre, R., et al.[2021]

Enzalutamide is an effective androgen receptor inhibitor that improves overall survival in patients with metastatic castration-resistant prostate cancer, showing a 4.8-month survival benefit in those previously treated with docetaxel, as demonstrated in the Phase III AFFIRM trial.

The FDA has expanded enzalutamide's approval to include first-line treatment for metastatic castration-resistant prostate cancer in patients who have not yet received chemotherapy, and it is associated with an acceptable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide for patients with metastatic castration-resistant prostate cancer. Ramadan, WH., Kabbara, WK., Al Basiouni Al Masri, HS.[2020]

In a study of 86 men with recurrent prostate cancer, combining enzalutamide (ENZA) with salvage radiation therapy (SRT) significantly improved freedom from prostate-specific antigen (PSA) progression, with a 2-year FFPP of 84% for ENZA compared to 66% for placebo.

The treatment was found to be safe, with common side effects including fatigue and urinary frequency, but the long-term effects on distant metastasis or overall survival are still unclear.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Randomized Study of Salvage Radiation Therapy Plus Enzalutamide or Placebo for High-Risk Prostate-Specific Antigen Recurrent Prostate Cancer After Radical Prostatectomy: The SALV-ENZA Trial. Tran, PT., Lowe, K., Tsai, HL., et al.[2023]

In a phase 2 trial involving 11 patients with high-risk localized prostate cancer, the combination of enzalutamide with standard androgen deprivation therapy and radiation therapy was found to be well-tolerated, with only one patient experiencing a severe adverse event (seizure).

All patients achieved a complete response in prostate-specific antigen (PSA) levels, with a median time to PSA complete response of 4.2 months, and at 24 months, none of the patients had a biochemical recurrence, indicating strong efficacy of the treatment regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of Enzalutamide to Leuprolide and Definitive Radiation Therapy Is Tolerable and Effective in High-Risk Localized or Regional Nonmetastatic Prostate Cancer: Results From a Phase 2 Trial. Shee, K., de la Calle, CM., Chang, AJ., et al.[2022]

In a phase 2 study involving 103 intermediate-risk prostate cancer patients, relugolix achieved effective castration rates of 95% and 82% for testosterone levels below 1.73 nmol/l and 0.7 nmol/l, respectively, within just 4 days of treatment.

Relugolix demonstrated a favorable safety profile similar to that of degarelix, with common side effects like hot flushes, and showed potential as an effective oral alternative to injectable androgen deprivation therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Oral Gonadotropin-releasing Hormone Receptor Antagonist Relugolix as Neoadjuvant/Adjuvant Androgen Deprivation Therapy to External Beam Radiotherapy in Patients with Localised Intermediate-risk Prostate Cancer: A Randomised, Open-label, Parallel-group Phase 2 Trial. Dearnaley, DP., Saltzstein, DR., Sylvester, JE., et al.[2023]

Relugolix (Orgovyx) is the first oral medication approved for treating advanced prostate cancer, functioning as a gonadotropin-releasing hormone receptor antagonist.

While effective, relugolix carries risks such as prolonging the QT interval and potential embryo-fetal toxicity, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First Oral Hormone for Treating Prostate Cancer. Aschenbrenner, DS.[2023]

In the phase III HERO trial, relugolix demonstrated a sustained castration rate of over 90% in men with advanced prostate cancer over 48 weeks, which was non-inferior to the traditional treatment with leuprolide, and showed potential superiority in exploratory analyses.

Relugolix is generally well tolerated and may have a lower risk of major adverse cardiac events compared to leuprolide, making it a promising oral treatment option for rapid testosterone suppression without the initial surge associated with other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relugolix: A Review in Advanced Prostate Cancer. Shirley, M.[2023]

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]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Enzalutamide: a novel anti-androgen with prolonged survival rate in CRPC patients. [2021]

2. England pubmed.ncbi.nlm.nih.gov

A phase II randomized placebo-controlled double-blind study of salvage radiation therapy plus placebo versus SRT plus enzalutamide with high-risk PSA-recurrent prostate cancer after radical prostatectomy (SALV-ENZA). [2021]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Enzalutamide for patients with metastatic castration-resistant prostate cancer. [2020]

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

Phase II Randomized Study of Salvage Radiation Therapy Plus Enzalutamide or Placebo for High-Risk Prostate-Specific Antigen Recurrent Prostate Cancer After Radical Prostatectomy: The SALV-ENZA Trial. [2023]

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

Addition of Enzalutamide to Leuprolide and Definitive Radiation Therapy Is Tolerable and Effective in High-Risk Localized or Regional Nonmetastatic Prostate Cancer: Results From a Phase 2 Trial. [2022]

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

The Oral Gonadotropin-releasing Hormone Receptor Antagonist Relugolix as Neoadjuvant/Adjuvant Androgen Deprivation Therapy to External Beam Radiotherapy in Patients with Localised Intermediate-risk Prostate Cancer: A Randomised, Open-label, Parallel-group Phase 2 Trial. [2023]

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

First Oral Hormone for Treating Prostate Cancer. [2023]

8. France pubmed.ncbi.nlm.nih.gov

Relugolix: A Review in Advanced Prostate Cancer. [2023]

9. Australia pubmed.ncbi.nlm.nih.gov

Enzalutamide-induced severe thrombocytopenia complicated by a seizure in a 76-year-old man with castration-resistant prostate cancer. [2022]