MDRT + ADT for Prostate Cancer

Overseen By Angela Y Jia, MD, PhD

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: Case Comprehensive Cancer Center

Must be taking: Hormone therapy

Must not be taking: Investigational agents

Disqualifiers: Castration resistant, Visceral 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

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

200 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to find out if giving radiation therapy (RT) to areas of metastatic prostate cancer at the time a participant is diagnosed will help control disease better than the usual treatment. This treatment is called metastasis-directed radiotherapy (MDRT). The usual treatment for prostate cancer that has spread to other parts of the body is to give lifelong treatment with hormone therapy (also known as androgen deprivation therapy or ADT). Participants may also be given prostate RT even if the disease is metastatic. Participants will receive hormone therapy (the standard treatment for prostate cancer) for 12 months. The hormone therapy agents may be taken by mouth or given as an injection. Participants will also have prostate RT. Up to 50 participants will have surgery to remove the prostate instead of having prostate RT. A portion of the participants will be randomized to receive MDRT to areas where the cancer has spread. For participants who have surgery to remove their prostate, they will be asked to allow tissue samples collected during the surgery to be sent to an outside lab for research tests and extra blood samples drawn for research tests before starting the study, and at the time the cancer becomes worse if applicable. Participation in the study will last approximately 12 months, and will be followed by their doctor for up to five years per standard of care. The main goal is to compare the efficacy of the standard of care (standard systemic therapy + definitive prostate-directed local therapy) versus the standard of care with metastasis-directed radiotherapy (MDRT) for consolidation of metastatic disease.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, it mentions that participants will receive hormone therapy for 12 months, which is the standard treatment for prostate cancer.

What data supports the effectiveness of the treatment MDRT + ADT for prostate cancer?

Research shows that combining androgen deprivation therapy (ADT) with radiation therapy improves survival and local control in patients with locally advanced prostate cancer compared to radiation alone. ADT is also standard care for metastatic prostate cancer, indicating its effectiveness in advanced stages. ^{1 2 3 4 5}

Is the combination of MDRT and ADT generally safe for humans?

Androgen deprivation therapy (ADT), a part of this treatment, is known to have several side effects, including potential cardiovascular risks, which have been highlighted in safety warnings. It's important for patients to be aware of these risks and discuss them with their healthcare provider. ^{1 5 6 7 8}

How is the MDRT + ADT treatment for prostate cancer different from other treatments?

MDRT + ADT for prostate cancer is unique because it combines androgen deprivation therapy (ADT), which reduces male hormones to slow cancer growth, with another treatment approach (MDRT) that is not specified in the research. This combination aims to improve outcomes and reduce side effects compared to traditional ADT methods like orchiectomy or LHRH agonists used alone. ^{1 5 9 10 11}

Research Team

Angela Y Jia, MD, PhD

Principal Investigator

University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center

Daniel E Spratt, MD

Principal Investigator

University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center

Eligibility Criteria

Men over 18 with newly diagnosed metastatic prostate cancer, who haven't had prior treatment for it and are fit enough for therapy (ECOG ≤1). They should have evidence of limited spread on scans and be able to start hormone therapy. Excluded are those with resistant cancer, other active cancers within 2 years, or serious health issues that could interfere with the study.

Inclusion Criteria

Ability to understand and the willingness to sign a written informed consent

My scans show 1-5 cancer spread areas in bones or lymph nodes outside the pelvis.

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

Exclusion Criteria

Participant is participating in a concurrent treatment protocol for cancer

Any condition that in the opinion of the investigator would preclude participation in this study

I have had treatment aimed at curing my prostate cancer.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive hormone therapy for 12 months and may undergo radiotherapy or surgery. A portion will receive metastasis-directed radiotherapy (MDRT).

12 months

Multiple visits for treatment administration

Follow-up

Participants are monitored for safety and effectiveness after treatment, with follow-up by their doctor for up to five years.

5 years

Treatment Details

Interventions

• Androgen deprivation therapy (ADT)
• Metastasis directed radiotherapy (MDRT)

Trial Overview The trial is testing if adding radiation (MDRT) to areas where prostate cancer has spread improves disease control compared to usual treatments alone. Usual care includes lifelong hormone therapy and possibly prostate RT or surgery. Participants will be randomly chosen to receive either standard care or standard plus MDRT.

Participant Groups

Group I: SOC + MDRT Experimental Treatment 4 Interventions

* Participants will receive the standard of care. Standard systemic therapy (SST) and definitive local therapy (radiotherapy \[RT\] or radical prostatectomy \[RP\]) are the standard of care for de novo oligometastatic prostate cancer. This arm will be used to compare to the experimental arm. * SST will begin 6 weeks of randomization and occur for 12 months. The definitive local therapy will be RT, with a small portion undergoing RP. Local therapy should be completed by the end of Week 20. * MDRT should be completed by the end of Week 24. Depending on the participant, there are different approaches to MDRT dosing and fraction size.

Group II: Standard of Care (SOC) Active Control 3 Interventions

* Participants will receive the standard of care. Standard systemic therapy (SST) and definitive local therapy (radiotherapy \[RT\] or radical prostatectomy \[RP\]) are the standard of care for de novo oligometastatic prostate cancer. This arm will be used to compare to the experimental arm. * SST will begin 6 weeks of randomization and occur for 12 months. The definitive local therapy will be RT, with a small portion undergoing RP. Local therapy should be completed by the end of Week 20.

Androgen deprivation therapy (ADT) is already approved in European Union, United States, Canada, Japan, Switzerland for the following indications:

Approved in European Union as Androgen deprivation therapy for:

• Prostate cancer
• Metastatic prostate cancer
• Locally advanced prostate cancer

Approved in United States as Androgen deprivation therapy for:

• Prostate cancer
• Metastatic prostate cancer
• Locally advanced prostate cancer

Approved in Canada as Androgen deprivation therapy for:

• Prostate cancer
• Metastatic prostate cancer
• Locally advanced prostate cancer

Approved in Japan as Androgen deprivation therapy for:

• Prostate cancer
• Metastatic prostate cancer
• Locally advanced prostate cancer

Approved in Switzerland as Androgen deprivation therapy for:

• Prostate cancer
• Metastatic prostate cancer
• Locally advanced prostate cancer

Who Is Running the Clinical Trial?

Case Comprehensive Cancer Center

Lead Sponsor

Trials

472

Recruited

33,400+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Findings from Research

Androgen deprivation therapy (ADT) is effective for managing symptoms of prostate cancer but can lead to significant side effects that worsen over time, and it does not improve survival in men with localized disease.

Neoadjuvant ADT combined with external beam radiation has been shown to enhance survival in men with locally advanced prostate cancer, while immediate adjuvant ADT does not provide benefits for most men after radical prostatectomy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The timing and extent of androgen deprivation therapy for prostate cancer: weighing the clinical evidence. Ginzburg, S., Albertsen, PC.[2019]

In a study of 992 prostate cancer patients, longer durations of androgen deprivation therapy (ADT) significantly improved overall survival for patients with Gleason grade group (GG) 4, while lifelong ADT was more beneficial for those with GG 5 disease.

The findings suggest that while both GG 4 and GG 5 patients benefit from ADT, the optimal duration of treatment differs, indicating a need for tailored approaches to maximize efficacy and minimize treatment duration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of Gleason Grade With Androgen Deprivation Therapy Duration and Survival Outcomes: A Systematic Review and Patient-Level Meta-analysis. Kishan, AU., Wang, X., Seiferheld, W., et al.[2022]

In a study of 373 intermediate-risk prostate cancer patients treated with radiotherapy over 14 years, those aged 70 or younger who received radiotherapy alone had a higher risk of biochemical failure compared to those who received combined radiotherapy and androgen deprivation therapy (ADT).

The results suggest that short-term ADT may be beneficial for younger patients with favorable intermediate-risk prostate cancer, as it improved biochemical relapse-free survival from 82.1% to 94.0% compared to radiotherapy alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiotherapy with or without androgen deprivation therapy in intermediate risk prostate cancer? Amit, U., Lawrence, YR., Weiss, I., et al.[2020]

Androgen deprivation therapy (ADT) combined with radiation therapy (RT) results in higher quality-adjusted life years (QALYs) compared to RT alone, indicating a better overall survival outcome despite potential increased toxicity from ADT.

Using two different analysis methods, QASAD and QASAP, the study found that RT + ADT provided slightly better quality-adjusted survival, suggesting that these methods can aid in making treatment decisions that balance survival benefits with quality of life considerations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative quality-adjusted survival analysis between radiation therapy alone and radiation with androgen deprivation therapy in patients with locally advanced prostate cancer: a secondary analysis of Radiation Therapy Oncology Group 85-31 with novel decision analysis methods. Ahn, S., Lee, M., Jeong, CW.[2022]

Current guidelines for androgen-deprivation therapy (ADT) in advanced prostate cancer set a testosterone target of <50 ng/dL, but emerging evidence suggests that a lower target of <20 ng/dL may be more prognostically relevant.

Despite the growing data supporting lower testosterone levels during ADT, there are no established clinical recommendations for measuring testosterone in routine practice, highlighting a gap in current treatment protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Management of testosterone in advanced hormone-sensitive prostate cancer: still up to date?] Zastrow, S., Mudra, TN., Suttmann, H.[2022]

Androgen deprivation therapy (ADT) is a key treatment for prostate cancer, enhancing the effectiveness of local therapies like radiation and providing significant relief for metastatic cases.

While ADT is effective, it can lead to adverse effects such as hot flashes, decreased bone density, metabolic changes, and gynecomastia, which require careful management and ongoing research to address.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of the side effects of androgen deprivation therapy in men with prostate cancer. Flaig, TW., Glodé, LM.[2019]

Androgen deprivation therapy (ADT) is effective for managing metastatic or recurrent prostate cancer but can lead to significant side effects, including changes in body composition, increased fracture risk, and insulin resistance.

Recent studies suggest that denosumab and toremifene citrate can help reduce fracture risk in men undergoing ADT, highlighting the importance of managing these adverse effects to improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Androgen deprivation therapy in prostate cancer: anticipated side-effects and their management. Kim, HS., Freedland, SJ.[2015]

A systematic review of 4141 patients from 8 randomized trials found that androgen deprivation therapy (ADT) does not increase the risk of cardiovascular death in men with unfavorable-risk, nonmetastatic prostate cancer.

ADT was associated with a significant reduction in prostate cancer-specific mortality (PCSM) and all-cause mortality, indicating it may improve overall survival outcomes for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: a meta-analysis of randomized trials. Nguyen, PL., Je, Y., Schutz, FA., et al.[2022]

Androgen deprivation therapy (ADT) is a key treatment for prostate cancer, but the best timing, duration, and type of ADT are still being researched.

Current first-line treatments include orchiectomy, LHRH agonists, and combined androgen blockade (CAB), with new combinations showing potential for better outcomes and reduced side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The truth is out there: an overall perspective on androgen deprivation. Hellerstedt, BA., Pienta, KJ.[2019]

Androgen deprivation therapy (ADT) significantly enhances biochemical control when combined with dose-escalated radiation therapy (RT) for prostate cancer, as supported by recent phase III studies.

There is now randomized evidence supporting the use of ADT alongside RT in patients who have undergone prostatectomy, highlighting its ongoing importance in prostate cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The use of Hormonal Therapy to Augment Radiation Therapy in Prostate Cancer: An Update. Kauffmann, G., Liauw, SL.[2018]

Androgen deprivation therapy (ADT), particularly using GnRH-agonists and GnRH-antagonists like leuprolide, degarelix, and relugolix, is effective in suppressing testosterone levels in prostate cancer treatment, with similar efficacy across these methods.

Oral relugolix may offer improved cardiovascular safety compared to other ADT options, although this finding is based on secondary analyses and should be interpreted cautiously.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances with androgen deprivation therapy for prostate cancer. Yu, EM., Aragon-Ching, JB.[2022]

References

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

The timing and extent of androgen deprivation therapy for prostate cancer: weighing the clinical evidence. [2019]

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

Association of Gleason Grade With Androgen Deprivation Therapy Duration and Survival Outcomes: A Systematic Review and Patient-Level Meta-analysis. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Radiotherapy with or without androgen deprivation therapy in intermediate risk prostate cancer? [2020]

4. Korea (South) pubmed.ncbi.nlm.nih.gov

Comparative quality-adjusted survival analysis between radiation therapy alone and radiation with androgen deprivation therapy in patients with locally advanced prostate cancer: a secondary analysis of Radiation Therapy Oncology Group 85-31 with novel decision analysis methods. [2022]

5. Germany pubmed.ncbi.nlm.nih.gov

[Management of testosterone in advanced hormone-sensitive prostate cancer: still up to date?] [2022]

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

Management of the side effects of androgen deprivation therapy in men with prostate cancer. [2019]

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

Androgen deprivation therapy in prostate cancer: anticipated side-effects and their management. [2015]

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

Association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: a meta-analysis of randomized trials. [2022]

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

The truth is out there: an overall perspective on androgen deprivation. [2019]

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

The use of Hormonal Therapy to Augment Radiation Therapy in Prostate Cancer: An Update. [2018]

11. England pubmed.ncbi.nlm.nih.gov

Advances with androgen deprivation therapy for prostate cancer. [2022]