Combination Therapy for Prostate Cancer

Recruiting at 2 trial locations

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Cyp17-lyase inhibitors, AR antagonists

Disqualifiers: Active infection, Uncontrolled hypertension, Autoimmune 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: 17

Duration: Up to 39 weeks

196 Participants Needed

Trial Summary

What is the purpose of this trial?

This randomized phase II trial studies the side effects and how well abiraterone acetate, prednisone, and apalutamide work with or without ipilimumab or cabazitaxel and carboplatin in treating patients with castration-resistant prostate cancer that has spread to other places in the body. Androgens can cause the growth of prostate cancer cells. Drugs, such as abiraterone acetate and apalutamide may lessen the amount of androgens made by the body. Immunotherapy with monoclonal antibodies, such as ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as prednisone, cabazitaxel, and carboplatin work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving abiraterone acetate, prednisone, and apalutamide with or without ipilimumab or cabazitaxel and carboplatin may be a better way to treat patients with castration-resistant prostate cancer that has spread to other places in the body.

Will I have to stop taking my current medications?

The trial requires that certain medications be stopped or substituted at least 4 weeks before starting, especially those that lower the seizure threshold. Additionally, any systemic therapy for prostate cancer, except specific allowed treatments, must be stopped 28 days before starting the trial.

What data supports the effectiveness of the drug combination therapy for prostate cancer?

Research shows that abiraterone acetate combined with prednisone improves survival in men with prostate cancer, especially when used with other treatments like androgen deprivation therapy. This combination has been shown to prolong life and delay disease progression in various studies. ^{1 2 3 4 5}

Is the combination therapy for prostate cancer generally safe for humans?

Abiraterone acetate, when used with prednisone, is generally considered safe for treating metastatic castration-resistant prostate cancer, though it can cause side effects like low potassium levels, high blood pressure, fluid retention, and liver issues. These side effects were relatively low in frequency in clinical trials. ^{1 4 6 7 8}

What makes the combination therapy for prostate cancer unique?

This combination therapy is unique because it uses multiple drugs, including abiraterone acetate, apalutamide, cabazitaxel, and carboplatin, which target different pathways in prostate cancer cells, potentially offering a more comprehensive approach to treatment compared to using a single drug. ^{1 4 9 10 11}

Research Team

Ana Aparicio

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

Men with advanced prostate cancer that is resistant to castration and has spread, who can provide consent, have adequate organ function (blood counts, liver enzymes), and are not on certain medications. They must have a low testosterone level due to surgery or ongoing treatment, be able to swallow pills, agree to use contraception if necessary, and allow tissue collection for studies.

Inclusion Criteria

Presence of metastatic disease documented on imaging studies (bone scan, computed tomography [CT] and/or magnetic resonance imaging [MRI] scans)

My cancer outside of bones is growing or new.

I am undergoing treatment to lower my testosterone levels below 50 ng/dL.

Exclusion Criteria

I have active or symptomatic viral hepatitis or chronic liver disease.

I haven't taken specific prostate cancer drugs or chemotherapy in the last year.

I do not have an active infection or a condition that prevents steroid use, and I do not have HIV/AIDS.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lead-in Phase

Patients receive abiraterone acetate, prednisone, and apalutamide for 8 weeks to assess serum marker decline

8 weeks

Weekly visits for monitoring

Treatment

Patients are assigned to different arms based on serum marker decline and receive various combinations of drugs

Up to 39 weeks

Every 3 weeks for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 4 years

Follow-up at 14 and 30 days, then every 6 months

Treatment Details

Interventions

• Abiraterone Acetate
• Apalutamide
• Cabazitaxel
• Carboplatin
• Ipilimumab
• Prednisone

Trial Overview The trial tests how well abiraterone acetate, prednisone, and apalutamide work together compared with the addition of ipilimumab or cabazitaxel plus carboplatin. It aims to see which combination is more effective in stopping tumor growth by reducing androgens or killing tumor cells directly.

Participant Groups

Group I: Arm 2B (abiraterone acetate, prednisone, ARN-509, ipilimumab) Experimental Treatment 5 Interventions

Patients receive abiraterone acetate PO daily, prednisone PO BID, and apalutamide PO daily. Patients also receive ipilimumab IV over 90 minutes on day 1 of courses 4-7. Courses repeat every 3 weeks in the absence of disease progression or unexpected toxicity.

Group II: Arm 2A (abiraterone acetate, prednisone, apalutamide) Experimental Treatment 4 Interventions

Patients receive abiraterone acetate PO daily, prednisone PO BID, and apalutamide PO daily in the absence of disease progression or unexpected toxicity.

Group III: Arm 3(abiraterone, prednisone, ARN509,cabazitaxel,carboplatin) Active Control 6 Interventions

Patients receive abiraterone acetate PO daily, prednisone PO BID, and apalutamide PO daily. Patients also receive cabazitaxel IV over 60 minutes and carboplatin IV, over 60 minutes on day 1 of courses 4-13. Courses repeat every 3 weeks in the absence of disease progression or unexpected toxicity.

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

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 phase 3 trial with 1088 patients, abiraterone acetate plus prednisone significantly improved overall survival compared to placebo plus prednisone, with a median survival of 34.7 months versus 30.3 months, indicating its efficacy in treating chemotherapy-naive castration-resistant prostate cancer.

The treatment was associated with a manageable safety profile, although there were some increased risks of grade 3-4 adverse events, such as cardiac disorders and elevated liver enzymes, suggesting that while effective, monitoring for side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Ryan, CJ., Smith, MR., Fizazi, K., et al.[2022]

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 involving 515 patients with hormone-sensitive prostate cancer, those receiving abiraterone acetate plus prednisone (AAP) alongside standard care reported a higher quality of life (QOL) compared to those receiving docetaxel plus standard care, with a mean difference of +3.9 points over two years.

The improvement in global-QOL scores for the AAP group was particularly significant during the first year, with increases of +5.7 points at one year and +8.3 points at two years, indicating that AAP may offer better patient-reported outcomes in terms of quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quality of Life in Men With Prostate Cancer Randomly Allocated to Receive Docetaxel or Abiraterone in the STAMPEDE Trial. Rush, HL., Murphy, L., Morgans, AK., et al.[2023]

In a study of 148 patients with metastatic castration-resistant prostate cancer, maintaining abiraterone acetate plus prednisone (AAP) during docetaxel treatment did not improve radiographic progression-free survival compared to docetaxel plus prednisone alone, with rates of 34.9% and 33.9% respectively after 12 months.

The combination of docetaxel and AAP resulted in significantly higher rates of severe neutropenia (59.6%) compared to docetaxel plus prednisone (27.7%), suggesting that continuing AAP may increase treatment-related risks without providing additional benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II randomised trial of abiraterone acetate plus prednisone in combination with docetaxel or docetaxel plus prednisone after disease progression to abiraterone acetate plus prednisone in patients with metastatic castration-resistant prostate cancer: The ABIDO-SOGUG trial. Climent, MA., Font, A., Durán, I., et al.[2022]

Abiraterone acetate significantly improves overall survival and radiographic progression-free survival in men with metastatic castration-resistant prostate cancer (CRPC) when combined with prednisone, based on results from a multinational phase III study involving men who had previously received docetaxel.

The treatment is generally well-tolerated, although it can cause side effects like hypokalaemia and hypertension; however, serious adverse events were relatively low in the phase III studies, indicating it is a viable option for managing metastatic CRPC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abiraterone acetate: a review of its use in patients with metastatic castration-resistant prostate cancer. Hoy, SM.[2021]

In a phase 3 trial involving 1199 patients, the addition of abiraterone acetate and prednisone to androgen-deprivation therapy significantly improved overall survival, with a median survival not reached in the abiraterone group compared to 34.7 months in the placebo group.

The study also showed that patients receiving abiraterone had a median radiographic progression-free survival of 33.0 months, compared to 14.8 months in the placebo group, indicating a strong benefit in delaying disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. Fizazi, K., Tran, N., Fein, L., et al.[2022]

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 phase II study involving 41 men with metastatic castration-resistant prostate cancer, increasing the dose of abiraterone acetate from 1000 mg to 2000 mg daily did not result in any significant clinical benefit, as no patients showed a prostate-specific antigen (PSA) decline of 30% or more after 12 weeks.

The study found that factors such as lower baseline circulating androgen levels and individual differences in drug metabolism may contribute to resistance against standard-dose abiraterone therapy, suggesting that simply increasing the dose is not an effective strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-Dose Abiraterone Acetate in Men With Castration Resistant Prostate Cancer. Friedlander, TW., Graff, JN., Zejnullahu, K., et al.[2018]

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. England pubmed.ncbi.nlm.nih.gov

Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. [2022]

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

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

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

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

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

Quality of Life in Men With Prostate Cancer Randomly Allocated to Receive Docetaxel or Abiraterone in the STAMPEDE Trial. [2023]

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

A phase II randomised trial of abiraterone acetate plus prednisone in combination with docetaxel or docetaxel plus prednisone after disease progression to abiraterone acetate plus prednisone in patients with metastatic castration-resistant prostate cancer: The ABIDO-SOGUG trial. [2022]

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

Abiraterone acetate: a review of its use in patients with metastatic castration-resistant prostate cancer. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of abiraterone acetate plus prednisolone in patients with early metastatic castration-resistant prostate cancer who failed first-line androgen-deprivation therapy: a single-arm, phase 4 study. [2021]

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

Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. [2022]

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

High-Dose Abiraterone Acetate in Men With Castration Resistant Prostate Cancer. [2018]