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

12 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Prostate cancer is a common cancer among men. There are several ways to treat it, including hormone blocking drugs, radiation therapy, and surgery. Researchers want to combine abiraterone and enzalutamide to see if there is a better way to treat prostate cancer. They also want to study a new radiotracer called 18F-DCFPyL, with the help of a scan called positron emission tomography/computed tomography (PET/CT) to see if there is a better way to detect prostate cancer. Objective: To develop improved techniques to localize and detect prostate cancer; and to develop new ways to treat prostate cancer Eligibility: Men ages 18 and older with prostate cancer that has not spread to other parts of the body Design: * Participants will have a medical evaluation to determine eligibility for the study. * Participants will take three different medications daily by mouth and receive two injections during the course of the study. * Participants will have a medical evaluation monthly (for 6 months) while taking the medications. * Participants will have prostate MRI and PET/CT scans before treatment, 2 months after starting treatment and again before surgery. The radiotracer will be given by injection about 2 hours before the whole-body scan. The PET/CT scan itself is about an hour. * Participants may be asked to do a biopsy before treatment and 2 months after starting treatment. * Participants will have a full medical evaluation before surgery to remove their prostate. * Participants will have a follow-up visit 3 months after surgery and then as needed. * Participants will be contacted once a year for their PSA and testosterone levels for 5 years...

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.

What data supports the effectiveness of the drug combination of androgen deprivation therapy, enzalutamide, and abiraterone for prostate cancer?

Research shows that combining abiraterone acetate with prednisolone or enzalutamide at the start of androgen deprivation therapy improves outcomes and survival in patients with metastatic prostate cancer. Additionally, both enzalutamide and abiraterone have proven survival benefits in men with metastatic castration-resistant prostate cancer. ^{1 2 3 4 5}

Is the combination of androgen deprivation therapy, enzalutamide, and abiraterone safe for humans?

Studies have shown that abiraterone and enzalutamide, when used for advanced prostate cancer, can be associated with metabolic (related to the body's chemical processes) and cardiovascular (heart-related) side effects. However, these medications are generally considered safe for use in humans, with their benefits often outweighing the risks in treating prostate cancer. ^{1 3 6 7 8}

How is the drug combination of Androgen Deprivation Therapy, Enzalutamide, and Abiraterone unique for prostate cancer treatment?

This drug combination is unique because it combines androgen deprivation therapy (which reduces male hormone levels) with two novel drugs, Enzalutamide and Abiraterone, that target androgen receptors in different ways, potentially improving survival in both metastatic and high-risk non-metastatic prostate cancer. ^{1 2 9 10 11}

Research Team

Fatima H Karzai, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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 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]

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]

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 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 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]

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]

References

1. England 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. [2023]

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

Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. [2023]

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

Results of a Real-world Study of Enzalutamide and Abiraterone Acetate With Prednisone Tolerability (REAAcT). [2021]

4. United States 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). [2022]

5. United States 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). [2023]

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

Abiraterone acetate: a guide to its use in metastatic castration-resistant prostate cancer. [2021]

7. Greece pubmed.ncbi.nlm.nih.gov

Efficacy of Novel Hormone Agents in the Treatment of Metastatic Castration-resistant Prostate Cancer: A Real-world Retrospective Study. [2022]

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

Risk of Metabolic and Cardiovascular Adverse Events With Abiraterone or Enzalutamide Among Men With Advanced Prostate Cancer. [2023]

9. England 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. [2023]

10. England 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. [2021]

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

The Effect of Time to Castration Resistance on Outcomes With Abiraterone and Enzalutamide in Metastatic Prostate Cancer. [2021]