Hormone + Radiation Therapy for Prostate Cancer

Recruiting in Palo Alto (17 mi)

+599 other locations

Overseen by Paul L Nguyen

Age: 18+

Sex: Male

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: NRG Oncology

Must be taking: Hormone therapy

Must not be taking: 5-alpha reductase inhibitors

Disqualifiers: Metastatic disease, Seizure disorder, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This phase III trial compares less intense hormone therapy and radiation therapy to usual hormone therapy and radiation therapy in treating patients with high risk prostate cancer and low gene risk score. This trial also compares more intense hormone therapy and radiation therapy to usual hormone therapy and radiation therapy in patients with high risk prostate cancer and high gene risk score. Apalutamide may help fight prostate cancer by blocking the use of androgen by the tumor cells. Radiation therapy uses high energy rays to kill tumor cells and shrink tumors. Giving a shorter hormone therapy treatment may work the same at controlling prostate cancer compared to the usual 24 month hormone therapy treatment in patients with low gene risk score. Adding apalutamide to the usual treatment may increase the length of time without prostate cancer spreading as compared to the usual treatment in patients with high gene risk score.

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

The trial protocol does not specify if you need to stop all current medications, but if you are taking a 5-alpha reductase inhibitor, you should stop it before randomization. Additionally, if you are in the Intensification Cohort, you must stop or substitute medications that lower the seizure threshold at least 30 days before randomization.

What data supports the effectiveness of the treatment involving hormone and radiation therapy for prostate cancer?

Research shows that combining hormone therapy with radiation can improve prostate cancer control. For instance, adding bicalutamide to radiotherapy significantly improves survival in locally advanced prostate cancer. Additionally, abiraterone acetate with prednisone has been shown to improve survival in metastatic cases. ^{1 2 3 4 5}

Is hormone and radiation therapy for prostate cancer safe for humans?

Abiraterone, used in hormone therapy for prostate cancer, can cause side effects like heart issues and muscle loss. It may also lead to hormonal imbalances, such as mineralocorticoid excess and adrenal insufficiency, when used with prednisone. ^{6 7 8 9 10}

How does the hormone and radiation therapy treatment for prostate cancer differ from other treatments?

This treatment combines hormone therapy with radiation therapy, using a variety of drugs like Abiraterone Acetate and Apalutamide, which are known for their effectiveness in blocking androgens (male hormones) that fuel prostate cancer growth. The combination aims to improve tumor control and survival rates compared to radiation alone, although it may come with more side effects. ^{2 5 11 12 13}

Research Team

Paul L Nguyen

Principal Investigator

NRG Oncology

Eligibility Criteria

Men over 18 with high-risk prostate cancer, no metastatic disease outside the pelvis, and a good performance status can join. They must have had no prior chemotherapy for prostate cancer in the last 3 years, no radical prostatectomy or pelvic radiotherapy, and not be on certain medications like 5-alpha reductase inhibitors at randomization.

Inclusion Criteria

High-risk disease defined as having at least one or more of the following: PSA > 20 ng/mL prior to starting ADT Note: Patients receiving a 5-alpha reductase inhibitor (ex. finasteride) at the time of enrollment are eligible. The baseline PSA value should be doubled for PSAs taken while on 5-alpha reductase inhibitors and the medication should be discontinued prior to randomization but a washout period is not required. cT3a-T4 by digital exam or imaging (American Joint Committee on Cancer [AJCC] 8th edition [Ed.]) Gleason score of 8-10 Node positive by conventional imaging with a short axis of at least 1.0 cm

My prostate cancer is aggressive (Gleason score 8-10).

My cancer has spread to my lymph nodes, which are enlarged.

Exclusion Criteria

Definitive radiologic evidence of metastatic disease outside of the pelvic nodes (M1a, M1b or M1c) on conventional imaging (i.e. bone scan, CT scan, MRI) Prior systemic chemotherapy within ≤ 3 years prior to registration; note that prior chemotherapy for a different cancer is allowed (completed > 3 years prior to registration Prior radical prostatectomy Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields Current use of 5-alpha reductase inhibitor. NOTE: If the alpha reductase inhibitor is stopped prior to randomization the patient is eligible History of any of the following: Seizure disorder Current severe or unstable angina New York Heart Association Functional Classification III/IV (Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification.) History of any condition that in the opinion of the investigator, would preclude participation in this study Evidence of any of the following at registration: Active uncontrolled infection requiring IV antibiotics Baseline severe hepatic impairment (Child Pugh Class C) Inability to swallow oral pills Any current condition that in the opinion of the investigator, would preclude participation in this study Prior pharmacologic androgen ablation for prostate cancer is allowed only if the onset of androgen ablation (both luteinizing hormone-releasing hormone [LHRH] agonist and oral anti-androgen) is ≤ 60 days prior to registration; Please note: baseline PSA must be obtained prior to the start of any ADT PRIOR TO STEP 2 RANDOMIZATION: Evidence of known gastrointestinal disorder affecting absorption of oral medications at registration For patients entering the Intensification Cohort ONLY: Presence of uncontrolled hypertension (persistent systolic blood pressure [BP] ≥ 160 mmHg or diastolic BP ≥ 100 mmHg). Subjects with a history of hypertension are allowed, provided that BP is controlled to within these limits by anti-hypertensive treatment

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants undergo radiation therapy over 2-11 weeks and receive androgen deprivation therapy (ADT) for 12 or 24 months, with or without apalutamide, depending on genomic risk score.

24 months

Regular visits as clinically indicated

Follow-up

Participants are monitored for safety and effectiveness after treatment, including imaging and blood sample collection.

Up to 13 years

Periodic visits as clinically indicated

Treatment Details

Interventions

• Abiraterone Acetate (Hormone Therapy)
• Apalutamide (Androgen Receptor Antagonist)
• Bicalutamide (Hormone Therapy)
• Buserelin (Hormone Therapy)
• Degarelix (Hormone Therapy)
• Flutamide (Hormone Therapy)
• Goserelin (Hormone Therapy)
• Histrelin (Hormone Therapy)
• Leuprolide (Hormone Therapy)
• Prednisone (Hormone Therapy)
• Radiation Therapy (Radiation)
• Triptorelin (Hormone Therapy)

Trial Overview The trial is testing less intense vs usual hormone therapy plus radiation for patients with low gene risk scores. For those with high gene risk scores, it's comparing more intense treatment (adding apalutamide) to usual care. The goal is to see if these approaches control cancer better without spreading.

Participant Groups

Group I: Arm IV (intensification study) Experimental Treatment 16 Interventions

Patients undergo RT over 2-11 weeks and receive ADT (consisting of either leuprolide, goserelin, triptorelin, degarelix, buserelin, histrelin, or relugolix) for 24 months in the absence of disease progression or unacceptable toxicity. Patients also receive apalutamide PO QD. Treatment repeats every 90 days for up to 8 cycles (24 months) in the absence of disease progression or unacceptable toxicity. Patients undergo bone scan, PET scan, CT scan, and MRI at screening and as clinically indicated and may optionally undergo blood sample collection throughout the study.

Group II: Arm II (de-intensification study) Experimental Treatment 17 Interventions

Patients undergo RT over 2-11 weeks and receive ADT (consisting of either leuprolide, goserelin, triptorelin, degarelix, buserelin, histrelin, or relugolix and bicalutamide or flutamide) for 12 months in the absence of disease progression or unacceptable toxicity. Patients undergo bone scan, PET scan, CT scan, and MRI at screening and as clinically indicated and may optionally undergo blood sample collection throughout the study.

Group III: Arm I (de-intensification study) Active Control 17 Interventions

Patients undergo RT over 2-11 weeks and receive ADT (consisting of either leuprolide, goserelin, triptorelin, degarelix, buserelin, histrelin, or relugolix and bicalutamide or flutamide) for 24 months in the absence of disease progression or unacceptable toxicity. Patients undergo bone scan, PET scan, CT scan, and MRI at screening and as clinically indicated and may optionally undergo blood sample collection throughout the study.

Group IV: Arm III (intensification study) Active Control 17 Interventions

Patients undergo RT over 2-11 weeks and receive ADT as in Arm I. Patients undergo bone scan, PET scan, CT scan, and MRI at screening and as clinically indicated and may optionally undergo blood sample collection throughout the study.

Abiraterone Acetate is already approved in Canada, Japan for the following indications:

Approved in Canada as Zytiga for:

• Metastatic castration-resistant prostate cancer
• Metastatic castration-sensitive prostate cancer

Approved in Japan as Zytiga for:

• Prostate cancer

Who Is Running the Clinical Trial?

NRG Oncology

Lead Sponsor

Trials

242

Recruited

105,000+

Stephanie Gaillard

NRG Oncology

Chief Medical Officer

MD from Johns Hopkins University

Norman Wolmark

NRG Oncology

Chief Executive Officer since 2023

MD from Harvard Medical School

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Findings from Research

A case study of a patient with castration-resistant prostate cancer showed that combining ablative stereotactic body radiation therapy with ongoing enzalutamide treatment resulted in a durable complete remission, despite prior progression on the medication.

This finding highlights the potential for innovative treatment strategies in advanced prostate cancer and suggests the need for further clinical trials to explore this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic body radiation therapy for the treatment of oligoprogression on androgen receptor targeted therapy in castration-resistant prostate cancer. Nguyen, TC., Bajwa, R., Bari, S., et al.[2020]

In a study of 1,370 patients with locally advanced prostate cancer, bicalutamide 150 mg combined with radiotherapy significantly improved progression-free survival (PFS) by 44% and overall survival by 35% compared to radiotherapy alone, indicating its efficacy as an adjuvant therapy.

Bicalutamide also showed a substantial reduction in the risk of prostate-specific antigen (PSA) progression by 59%, making it a promising non-castration-based treatment option that offers quality-of-life benefits over traditional castration therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The addition of bicalutamide 150 mg to radiotherapy significantly improves overall survival in men with locally advanced prostate cancer. See, WA., Tyrrell, CJ.[2018]

In a phase 1 study involving men with rising PSA after prostate surgery, the combination of abiraterone acetate (AA) and goserelin with salvage radiotherapy (SRT) was found to have a recommended dose of 750 mg, as higher doses led to significant liver enzyme elevations in some patients.

While AA combined with SRT and goserelin did not increase pelvic toxicity, it unexpectedly resulted in a high frequency of grade 3 liver toxicity, highlighting the need for careful monitoring of liver function in patients receiving this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined abiraterone acetate plus prednisone, salvage prostate bed radiotherapy and LH-RH agonists (CARLHA-GEP12) in biochemically-relapsing prostate cancer patients following prostatectomy: A phase I study of the GETUG/GEP. Supiot, S., Campion, L., Pommier, P., et al.[2022]

In a phase 3 trial involving 806 patients with metastatic castration-resistant prostate cancer, the addition of radium-223 to abiraterone acetate and prednisone did not improve symptomatic skeletal event-free survival compared to placebo, indicating that this combination may not be effective for this patient group.

The radium-223 group experienced a significantly higher rate of bone fractures (29%) compared to the placebo group (11%), raising safety concerns about the use of this treatment combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. Smith, M., Parker, C., Saad, F., et al.[2020]

Abiraterone, when used with prednisone, improves overall and disease-free survival in patients with both castration-resistant and castration-sensitive prostate cancer.

In a case series of 3 patients, it was found that abiraterone can lead to mineralocorticoid excess and secondary adrenal insufficiency, highlighting the need for awareness and management of these endocrine side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abiraterone-Induced Endocrinopathies. Decamps, S., Lis, R., Ekanayake, P.[2023]

Abiraterone is associated with a significantly higher risk of atrial tachyarrhythmia (AT) and heart failure (HF) compared to enzalutamide and other androgen deprivation therapies, with reporting odds ratios of 4.1 and 2.5 respectively, based on a large analysis of over 5.7 million adverse drug reaction reports.

The onset of AT and HF occurs more quickly in patients taking abiraterone, with mean times of 5.2 and 4.5 months, respectively, indicating a potential safety concern linked to its mechanism of inducing hypermineralocorticism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Heart failure and atrial tachyarrhythmia on abiraterone: A pharmacovigilance study. Bretagne, M., Lebrun-Vignes, B., Pariente, A., et al.[2021]

In a study of 55 patients with metastatic hormone-naive prostate cancer, no significant differences in muscle loss were observed between those receiving androgen deprivation therapy (ADT) alone or in combination with either abiraterone or enzalutamide.

Despite the lack of difference between treatment groups, all patients experienced decreases in skeletal muscle mass, emphasizing the need for strategies to preserve muscle during ADT for prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of the sarcopenic effect of androgen receptor-axis-targeted agents vs. androgen deprivation alone in patients with metastatic prostate cancer. Lawen, T., Masoumi-Ravandi, K., Rendon, RA., et al.[2023]

In a study of 60 patients with metastatic castration-resistant prostate cancer, combining radium-223 with either abiraterone or enzalutamide did not improve overall survival compared to radium-223 alone, with median survival times of 12.7 and 12.8 months respectively.

However, the combination treatment did significantly extend progression-free survival (7.6 months vs. 4.9 months), without increasing the risk of serious adverse events, suggesting a potential benefit in delaying disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A real-world evaluation of radium-223 in combination with abiraterone or enzalutamide for the treatment of metastatic castration-resistant prostate cancer. Kim, SI., Szeto, AH., Morgan, KP., et al.[2021]

A study involving 32 healthy male subjects demonstrated that the test product (abiraterone acetate tablet) is bioequivalent to the reference product ZYTIGA® in terms of pharmacokinetics, with both products showing similar maximum concentration (Cmax) and area under the curve (AUC) values within the acceptable range.

The research confirmed significant intra-subject variability in the pharmacokinetics of abiraterone, indicating that individual responses to the drug can vary widely, which is important for clinicians to consider when prescribing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and bioequivalence of generic and branded abiraterone acetate tablet: a single-dose, open-label, and replicate designed study in healthy Chinese male volunteers. Wang, C., Hu, C., Gao, D., et al.[2022]

Recent studies from major screening trials (ERSPC and PLCO) have highlighted the importance of early detection and prevention strategies in prostate cancer, influencing clinical practices.

Combination therapies involving hormonal and radiation treatments have been shown to significantly reduce recurrence and mortality rates in patients with locally advanced prostate cancer, while new drugs like abiraterone and MDV 3100 offer promising options for castrate-resistant cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[What's new in 2009 in prostate cancer: highlights from ASTRO, EAU, ASCO and AUA meetings]. Salomon, L., Peyromaure, M., Mongiat-Artus, P., et al.[2010]

Combining hormone therapy with radiotherapy for prostate cancer provides a biochemical survival advantage in nearly all cases of non-metastatic disease, highlighting the effectiveness of this treatment strategy.

More research is necessary to determine the best patient populations, specific combinations of treatments, and optimal duration of hormone therapy to maximize benefits for patients with prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effectiveness of combining hormone therapy and radiotherapy in the treatment of prostate cancer. Jani, AB.[2019]

Combining radiotherapy with hormonal therapy for locally advanced prostate cancer can improve local tumor remission rates and reduce tumor progression compared to radiotherapy alone, although it has not yet shown a significant improvement in overall survival rates.

The timing of hormonal therapy is crucial, as administering it before radiotherapy can reduce tumor size and enhance treatment effectiveness, particularly for patients with voiding problems, but more controlled studies are needed to fully evaluate this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The combined radiation and hormonal therapy of prostatic carcinoma: a conceptual analysis]. Sommerkamp, H., Slanina, J.[2006]

References

1. England pubmed.ncbi.nlm.nih.gov

Stereotactic body radiation therapy for the treatment of oligoprogression on androgen receptor targeted therapy in castration-resistant prostate cancer. [2020]

2. Germany pubmed.ncbi.nlm.nih.gov

The addition of bicalutamide 150 mg to radiotherapy significantly improves overall survival in men with locally advanced prostate cancer. [2018]

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

Combined abiraterone acetate plus prednisone, salvage prostate bed radiotherapy and LH-RH agonists (CARLHA-GEP12) in biochemically-relapsing prostate cancer patients following prostatectomy: A phase I study of the GETUG/GEP. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. [2020]

5. 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]

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

Abiraterone-Induced Endocrinopathies. [2023]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Heart failure and atrial tachyarrhythmia on abiraterone: A pharmacovigilance study. [2021]

8. Canada pubmed.ncbi.nlm.nih.gov

A comparison of the sarcopenic effect of androgen receptor-axis-targeted agents vs. androgen deprivation alone in patients with metastatic prostate cancer. [2023]

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

A real-world evaluation of radium-223 in combination with abiraterone or enzalutamide for the treatment of metastatic castration-resistant prostate cancer. [2021]

10. Germany pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and bioequivalence of generic and branded abiraterone acetate tablet: a single-dose, open-label, and replicate designed study in healthy Chinese male volunteers. [2022]

11. France pubmed.ncbi.nlm.nih.gov

[What's new in 2009 in prostate cancer: highlights from ASTRO, EAU, ASCO and AUA meetings]. [2010]

12. England pubmed.ncbi.nlm.nih.gov

The effectiveness of combining hormone therapy and radiotherapy in the treatment of prostate cancer. [2019]

13. Germany pubmed.ncbi.nlm.nih.gov

[The combined radiation and hormonal therapy of prostatic carcinoma: a conceptual analysis]. [2006]