Hormone + Radiation Therapy for Prostate Cancer

Recruiting at 668 trial locations

Overseen By Nataniel H. Lester-Coll

Age: 18+

Sex: Male

Trial Phase: Phase 3

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: 24 months

2753 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores different combinations of hormone therapy and radiation therapy for treating high-risk prostate cancer. Researchers compare shorter hormone treatments with the usual 24-month treatments for patients with a low genetic risk and test whether adding apalutamide, a hormone therapy, benefits patients with a high genetic risk. The goal is to find the best way to prevent cancer from spreading while minimizing side effects. Individuals with high-risk prostate cancer, such as those with a PSA level over 20 or a Gleason score of 8-10, might be suitable for this trial. As a Phase 3 trial, this study represents the final step before FDA approval, offering patients a chance to contribute to potentially groundbreaking treatment advancements.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that treatments like apalutamide, when combined with hormone therapy, are generally well-tolerated by prostate cancer patients. One study found that about 20% of patients experienced serious side effects, similar to those who received only hormone therapy. This indicates that adding apalutamide does not significantly increase severe side effects.

Hormone therapies such as leuprolide and goserelin, included in this trial, have been commonly used and are usually well-tolerated, as previous studies have indicated. These are standard treatments for prostate cancer, and while side effects can occur, they are typically manageable.

Overall, the treatments tested in this trial have a strong safety record. Although any treatment can have side effects, research suggests these are generally manageable and similar to those seen with current standard prostate cancer treatments. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for prostate cancer because they explore different approaches to hormone therapy combined with radiation. Unlike the standard of care that typically includes longer hormone therapy durations, the de-intensification study arms examine the potential benefits of shorter hormone therapy durations (12 months) with radiation, which could mean fewer side effects for patients. On the other hand, the intensification study arms add apalutamide, an androgen receptor inhibitor, which may enhance the treatment's effectiveness by blocking cancer cell growth more comprehensively. This trial could lead to more personalized and effective treatment strategies for prostate cancer patients.

What evidence suggests that this trial's treatments could be effective for prostate cancer?

Research shows that apalutamide, one of the treatments in this trial, is promising for treating prostate cancer when combined with androgen deprivation therapy (ADT). Studies indicate that this combination can lower the risk of death by 23% in patients with metastatic castration-sensitive prostate cancer over two years. Furthermore, patients taking apalutamide with ADT have a higher survival rate at four years compared to those taking a placebo with ADT. This suggests that adding apalutamide to standard hormone therapy can enhance treatment effectiveness, especially for those at high genetic risk of cancer spreading.

In this trial, some participants will receive ADT alone, a key treatment for prostate cancer for many years. ADT works by reducing male hormones that can help cancer grow. Combining ADT with radiation therapy, as done in various arms of this trial, has successfully managed and controlled high-risk prostate cancer. These treatments aim to improve outcomes while minimizing side effects, whether the treatment is intensified or reduced. ^{6 7 8 9 10}

Who Is on the Research Team?

Paul L Nguyen

Principal Investigator

NRG Oncology

Are You a Good Fit for This Trial?

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Abiraterone Acetate
• Apalutamide
• Bicalutamide
• Buserelin
• Degarelix
• Flutamide
• Goserelin
• Histrelin
• Leuprolide
• Prednisone
• Radiation Therapy
• Triptorelin

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.

How Is the Trial Designed?

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 United States, European Union, Canada, Japan for the following indications:

Approved in United States as Zytiga for:

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

Approved in European Union as Zytiga for:

• Metastatic castration-resistant prostate cancer
• Newly diagnosed high-risk metastatic hormone-sensitive prostate cancer

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+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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 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 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 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]

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]

Citations

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ERLEADA® (apalutamide) demonstrates statistically ... Largest head-to-head real-world study in mCSPC demonstrated that ERLEADA® reduced risk of death by 23 percent at 24 months compared to ...

2. erleadahcp.com erleadahcp.com/efficacy/

Efficacy | ERLEADA® (apalutamide) HCP Median follow-up time was 44.0 months. 1. The survival rate at 48 months was 65.1% for ERLEADA ® + ADT patients vs 51.8% for placebo + ADT patients.

3. nature.com nature.com/articles/s41391-024-00929-6

Survival outcomes of apalutamide as a starting treatment Starting treatment with APA + ADT was associated with a significantly reduced risk of death compared with ENZ + ADT (aHR, 95%CI) (0.66, 0.51– ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39893578/

Real-world clinical usage and efficacy of apalutamide in ... The secondary outcomes were the efficacy of apalutamide: PSA response (50% or 90% decline), progression-free survival, and skin-adverse events ( ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S2588931124002530

Apalutamide in Metastatic Castration-sensitive Prostate ... Our results show that apalutamide is a safe and effective drug in the real-world setting as well as in clinical trials.

6. erleadahcp.com erleadahcp.com/safety/

Safety | ERLEADA® (apalutamide) HCP Serious adverse reactions occurred in 20% of patients in the ERLEADA® + ADT arm and 20% of patients in the placebo + ADT arm.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5543693/

Safety and Antitumor Activity of Apalutamide (ARN-509) in ... Apalutamide was safe, well tolerated, and demonstrated clinical activity in mCRPC with 80% of AAP-naïve and 43% of post-AAP patients remaining on treatment for ...

8. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2024/210951s017lbl.pdf

ERLEADA® (apalutamide) tablets, for oral use In a randomized study (TITAN) of patients with metastatic castration-sensitive prostate cancer, fractures occurred in 9% of patients treated with ERLEADA and in ...

9. erleada.com erleada.com/

Official Patient Website | ERLEADA® (apalutamide) ERLEADA is a prescription medicine used to treat two types of prostate cancer: Prostate cancer that HAS SPREAD to other parts of the body and STILL responds to ...

10. innovativemedicine.jnj.com innovativemedicine.jnj.com/us/news-center/oncology/erleada-apalutamide-demonstrates-statistically-significant-and-clinically-meaningful-improvement-in-overall-survival-compared-to-enzalutamide-in-patients-with-metastatic-castration-sensitive-prostate-cancer

ERLEADA® (apalutamide) demonstrates statistically ... Largest head-to-head real-world study in mCSPC demonstrated that ERLEADA® reduced risk of death by 23 percent at 24 months compared to ...