Androgen Deprivation Therapy + Enzalutamide + Abiraterone for Prostate Cancer

Overseen By Fatima H Karzai, M.D.

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must be taking: Enzalutamide, Abiraterone

Must not be taking: Antiretrovirals, CYP3A4 inhibitors

Disqualifiers: Metastatic disease, Cardiac 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: 6

Duration: 6 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to improve the detection and treatment of prostate cancer by combining three medications and using a PET/CT scan. The research examines the effectiveness of combining abiraterone and enzalutamide, two hormone-blocking drugs, with a new radiotracer to enhance cancer treatment and detection. Men with non-metastatic prostate cancer who have not received prior treatments are suitable candidates for this trial. Participants will take medications, undergo scans, and possibly have surgery to evaluate the effectiveness of these methods. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as strong inhibitors or inducers of CYP3A4 or PgP, and medications for urinary symptoms like 5-alpha reductase inhibitors and alternative medications that alter PSA. If you are on these, you will need to stop them before joining the trial.

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

Research has shown that enzalutamide and abiraterone are common treatments for prostate cancer. These drugs have been studied separately and are usually well-tolerated. However, using them together might increase the chance of side effects. For example, one study found that combining these drugs with therapy that blocks male hormones is not recommended for long-term use due to the risk of serious side effects.

When taken alone, abiraterone or enzalutamide can cause side effects like tiredness, high blood pressure, and liver problems, which are generally manageable. Regular check-ups are important for participants to monitor these effects.

This trial is in Phase 2, aiming to assess the effectiveness and safety of the new treatment. Phase 2 trials provide more information about safety, though they are not as detailed as later trials. Researchers will closely monitor participants to ensure their safety throughout the study. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of androgen deprivation therapy, Enzalutamide, and Abiraterone for prostate cancer because it targets the disease from multiple angles. Unlike traditional treatments that may focus on just one pathway to reduce androgen levels, this combination approach simultaneously blocks androgen production and receptor activation. This multi-pronged attack prevents the cancer cells from using androgen hormones to grow and spread. By combining these therapies, there's potential for a more comprehensive treatment that could improve outcomes for patients compared to standard options like surgery or radiation alone.

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

Research shows that combining the drugs abiraterone and enzalutamide may help treat prostate cancer. In this trial, participants will receive both medications as part of the treatment regimen. Abiraterone has significantly increased the time patients live without their cancer worsening, with an average of 33 months compared to 14.8 months for those not taking it. Enzalutamide lowers the chance of cancer progression by 61%. Both medications block hormones that help prostate cancer grow. These findings suggest that using both treatments together could effectively manage prostate cancer. ^{2 6 7 8 9}

Who Is on the Research Team?

Fatima H Karzai, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

Men 18+ with untreated prostate cancer that hasn't spread beyond regional lymph nodes. They must have a Gleason score of 7 or higher, normal organ function tests, and be eligible for surgery to remove the prostate. Participants need to agree to use contraception and attend follow-up visits at NIH.

Inclusion Criteria

My kidney function, measured by creatinine clearance, is adequate.

- creatinine within normal institutional limits; OR,

My prostate cancer diagnosis has been confirmed by a certified lab.

Exclusion Criteria

I am not taking medications for urinary symptoms or any that affect PSA levels while on enzalutamide and abiraterone.

I cannot take steroids due to health reasons.

- PT/PTT greater than or equal to 1.5 times the upper limit of normal

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 receive androgen deprivation therapy combined with enzalutamide and abiraterone for 6 months

6 months

Monthly medical evaluations (in-person)

Imaging and Biopsy

Participants undergo prostate MRI and PET/CT scans, and may have biopsies before treatment, 2 months after starting treatment, and before surgery

6 months

3 imaging sessions (in-person)

Surgery

Participants undergo radical prostatectomy after 6 months of treatment

1 week

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after surgery, with a follow-up visit 3 months post-surgery and annual contact for PSA and testosterone levels for 5 years

5 years

1 visit (in-person) at 3 months, annual contact

What Are the Treatments Tested in This Trial?

Interventions

• 18F-DCFPyL
• Abiraterone
• Enzalutamide
• Goserelin
• Prednisone
• Radical Prostatectomy

Trial Overview The trial is testing a combination of hormone-blocking drugs (abiraterone and enzalutamide) along with a new radiotracer (18F-DCFPyL) used in PET/CT scans for better detection and treatment of localized prostate cancer.

How Is the Trial Designed?

Group I: 1 Experimental Treatment 6 Interventions

Treatment

Abiraterone 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 (mCRPC)
• Metastatic high-risk castration-sensitive prostate cancer (mCSPC)

Approved in European Union as Zytiga for:

• Metastatic castration-resistant prostate cancer (mCRPC)
• Metastatic high-risk castration-sensitive prostate cancer (mCSPC)

Approved in Canada as Zytiga for:

• Metastatic castration-resistant prostate cancer (mCRPC)
• Metastatic high-risk castration-sensitive prostate cancer (mCSPC)

Approved in Japan as Zytiga for:

• Metastatic castration-resistant prostate cancer (mCRPC)
• Metastatic high-risk castration-sensitive prostate cancer (mCSPC)

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study involving 1974 men with high-risk non-metastatic prostate cancer, combination therapy with abiraterone acetate and prednisolone significantly improved metastasis-free survival compared to androgen-deprivation therapy (ADT) alone, with a hazard ratio of 0.53, indicating a 47% reduction in the risk of metastasis.

The combination therapy also showed significant improvements in overall survival, prostate cancer-specific survival, and biochemical failure-free survival, although it was associated with a higher incidence of grade 3 or higher adverse events, such as hypertension and liver enzyme elevation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol. Attard, G., Murphy, L., Clarke, NW., et al.[2023]

In a study of 80 patients with metastatic castration-resistant prostate cancer, a shorter time to castration resistance during primary androgen deprivation therapy (ADT) was linked to poorer progression-free survival (PFS) and overall survival after starting treatment with abiraterone or enzalutamide.

Despite the association, the time to castration resistance was not an independent predictor of survival or prostate-specific antigen (PSA) response when analyzed with other factors, suggesting that while it may indicate initial treatment outcomes, it does not determine the effectiveness of subsequent AR-targeting therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effect of Time to Castration Resistance on Outcomes With Abiraterone and Enzalutamide in Metastatic Prostate Cancer. Hung, J., Taylor, AR., Divine, GW., et al.[2021]

In a study of 100 patients with metastatic castration-resistant prostate cancer, those treated with enzalutamide (ENZA) reported significantly more fatigue and neurocognitive issues compared to those treated with abiraterone acetate plus prednisone (AA+P).

While both treatments had similar rates of severe adverse events, ENZA was associated with unique neuropsychiatric side effects such as memory impairment and confusion, indicating a need for careful monitoring of cognitive function in patients receiving this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Results of a Real-world Study of Enzalutamide and Abiraterone Acetate With Prednisone Tolerability (REAAcT). Shore, ND., Saltzstein, D., Sieber, P., et al.[2021]

In a study involving 1,311 men with metastatic castration-resistant prostate cancer, the addition of abiraterone acetate and prednisone to enzalutamide did not significantly improve overall survival compared to enzalutamide alone, with median survival times of 32.7 months versus 34.2 months, respectively.

However, the combination treatment did result in longer radiographic progression-free survival (24.3 months vs. 21.3 months), indicating some benefit in delaying disease progression, although increased clearance of abiraterone when combined with enzalutamide may have influenced these outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized Phase III Study of Enzalutamide Compared With Enzalutamide Plus Abiraterone for Metastatic Castration-Resistant Prostate Cancer (Alliance A031201 Trial). Morris, MJ., Heller, G., Hillman, DW., et al.[2023]

In a study involving 1917 men with locally advanced or metastatic prostate cancer, the combination of abiraterone acetate and prednisolone with androgen-deprivation therapy (ADT) significantly improved overall survival compared to ADT alone, with a hazard ratio of 0.63, indicating a 37% reduction in the risk of death.

The combination therapy also resulted in a much lower rate of treatment failure, with a hazard ratio of 0.29, meaning patients were less likely to experience disease progression compared to those receiving only ADT, although it was associated with a higher incidence of grade 3 to 5 adverse events (47% vs. 33%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. James, ND., de Bono, JS., Spears, MR., et al.[2023]

Oral abiraterone acetate (Zytiga®) significantly improves overall survival and progression-free survival in patients with metastatic castration-resistant prostate cancer (CRPC) when used with prednisone, compared to a placebo.

The treatment is specifically effective for patients who have already undergone docetaxel-containing chemotherapy, highlighting its role as a subsequent therapy in advanced prostate cancer management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abiraterone acetate: a guide to its use in metastatic castration-resistant prostate cancer. Scott, LJ., Yang, LPH., Lyseng-Williamson, KA.[2021]

In a study of 143 men with metastatic castration-resistant prostate cancer, those treated with Enzalutamide (ENZ) experienced significantly longer biochemical progression-free survival compared to those treated with Abiraterone acetate plus Prednisone (AA+P), with a hazard ratio of 0.54.

There was no significant difference in overall survival between the two treatment groups, indicating that while ENZ may delay disease progression, it does not necessarily extend overall survival compared to AA+P.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abiraterone acetate plus Prednisone/Prednisolone compared with Enzalutamide in metastatic castration resistant prostate cancer before or after chemotherapy: A retrospective study of real-world data (ACES). Das, P., Taylor, S., Price, J., et al.[2022]

In a study involving 1919 patients with metastatic prostate cancer, the addition of abiraterone acetate to standard androgen deprivation therapy significantly improved overall survival, with a median survival of 76.6 months compared to 45.7 months for standard care alone.

Combining both abiraterone and enzalutamide did not provide additional survival benefits over abiraterone alone, and it was associated with higher rates of severe side effects, suggesting that this combination should be avoided in long-term treatment plans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abiraterone acetate plus prednisolone with or without enzalutamide for patients with metastatic prostate cancer starting androgen deprivation therapy: final results from two randomised phase 3 trials of the STAMPEDE platform protocol. Attard, G., Murphy, L., Clarke, NW., et al.[2023]

Men with advanced prostate cancer taking abiraterone have a significantly higher risk of major metabolic or cardiovascular adverse events compared to those not on the medication, with a hazard ratio of 1.77.

Enzalutamide also increases the risk of major adverse events, but to a lesser extent (hazard ratio of 1.22), and does not significantly increase the risk of minor adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk of Metabolic and Cardiovascular Adverse Events With Abiraterone or Enzalutamide Among Men With Advanced Prostate Cancer. Lai, LY., Oerline, MK., Caram, MEV., et al.[2023]

In a study involving 202 patients with metastatic castration-resistant prostate cancer, the sequence of treatment with abiraterone acetate followed by enzalutamide resulted in a longer time to second PSA progression (19.3 months) compared to the reverse sequence (15.2 months), indicating a more effective treatment strategy.

Enzalutamide demonstrated a significantly higher PSA response rate (36%) as a second-line therapy compared to abiraterone (4%), suggesting that enzalutamide is more effective when used after abiraterone in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimal sequencing of enzalutamide and abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase 2, crossover trial. Khalaf, DJ., Annala, M., Taavitsainen, S., et al.[2021]

Citations

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Real-World Safety and Efficacy Outcomes with Abiraterone ... Abiraterone acetate plus prednisone or prednisolone (AAP) prolongs survival in chemotherapy-naive and docetaxel-experienced patients.

2. e-juo.org e-juo.org/journal/view.php?number=594

Assessing Patient Risk, Benefit, and Outcomes in Drug ... Nearly all clinical trials testing abiraterone in prostate cancer showed promising outcomes with 89% of studies meeting their endpoint.

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Abiraterone plus Prednisone in Metastatic, Castration- ... The median length of radiographic progression-free survival was 33.0 months in the abiraterone group and 14.8 months in the placebo group ( ...

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Metastatic High-Risk CSPC LATITUDE Study A major efficacy outcome was overall survival. The pre-specified interim analysis after 406 deaths showed a statistically significant improvement in OS in ...

5. nature.com nature.com/articles/s41391-024-00816-0

Real-world overall survival with abiraterone acetate versus ... 1L abiraterone was associated with worse OS versus enzalutamide in the overall population and among subgroups with older age and comorbidities.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12504157/

Comparative effectiveness and safety of enzalutamide ... The median overall survival of pre-docetaxel abiraterone and enzalutamide was 36.1 and 39.9 months, respectively. In contrast, the median ...

7. ascopubs.org ascopubs.org/doi/abs/10.1200/JCO.2025.43.5_suppl.367

Real-world discontinuation and efficacy data of abiraterone ... Background: Data from STAMPEDE trial confirmed Overall survival benefit for patients with high-risk localized or locally advanced prostate ...

8. thelancet.com thelancet.com/journals/lanonc/article/PIIS1470-2045(23)00148-1/fulltext

Abiraterone acetate plus prednisolone with or without ... Enzalutamide and abiraterone should not be combined for patients with prostate cancer starting long-term androgen deprivation therapy. Clinically important ...

9. sciencedirect.com sciencedirect.com/science/article/pii/S1558767324001563

Outcomes of First-Line Abiraterone Acetate or ... Of the 337 patients identified, 24 (7.1%) received ADT+D and 313 (92.9%) received ADT alone for mCSPC. Median follow-up from AA/Enza start was 18.8 months.