Combination Therapy for Prostate Cancer

Recruiting at 1 trial location

Age: 18+

Sex: Male

Trial Phase: Phase 1

Sponsor: Weill Medical College of Cornell University

Must be taking: LHRH/GnRH analogue

Must not be taking: Azoles, CYP3A4 inducers

Disqualifiers: Liver disease, Brain metastases, others

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

Compensation: Varies

Number of Visits: 15

Duration: 6 weeks for initial dose-limiting toxicity assessment

16 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a multi-center, Phase I study of apalutamide in combination with abiraterone acetate, docetaxel and prednisone in patients with metastatic mastrate resistant prostate cancer (mCRPC). This study is designed to determine the dose that apalutamide can be administered safely in combination with abiraterone acetate, docetaxel and prednisone.

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

The trial requires that you stop taking medications known to lower the seizure threshold at least 4 weeks before starting the study drug. Herbal, alternative, and food supplements must also be discontinued before treatment starts. If you are on a stable dose of bisphosphonates or Denosumab, you may continue these medications.

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

Research shows that abiraterone acetate, when combined with prednisone, significantly extends survival and delays disease progression in patients with advanced prostate cancer. Additionally, apalutamide has been shown to improve survival and maintain quality of life in patients with prostate cancer, making these drugs effective components of combination therapy. ^{1 2 3 4 5}

Is the combination therapy for prostate cancer safe for humans?

The combination of abiraterone acetate (Zytiga) with prednisone has been used safely in patients with metastatic castration-resistant prostate cancer. While it can cause side effects like low potassium levels, high blood pressure, fluid retention, and liver issues, these were relatively low in frequency and considered manageable in clinical trials. ^{1 6 7 8 9}

What makes the combination therapy of Abiraterone acetate and Apalutamide unique for prostate cancer?

This combination therapy is unique because it combines two oral medications, Abiraterone acetate and Apalutamide, which target different aspects of prostate cancer. Abiraterone acetate inhibits an enzyme crucial for testosterone production, while Apalutamide blocks the androgen receptor, both of which are important in prostate cancer growth. ^{1 3 6 7 10}

Research Team

Ana Molina, MD

Principal Investigator

Weill Medical College of Cornell University

Eligibility Criteria

Men over 18 with advanced prostate cancer that's resistant to hormone therapy can join. They need a certain level of health, like normal organ/marrow function and controlled blood pressure. They must not have had recent heart issues, seizures, or certain treatments like chemotherapy for prostate cancer within the last 3 years.

Inclusion Criteria

Ability to understand and willingness to sign a written informed consent document

My prostate cancer was confirmed by a lab test.

My testosterone levels are below 50 ng/dL, and I am on hormone therapy unless I've had an orchiectomy.

Exclusion Criteria

I have moderate to severe nerve damage.

I have previously been treated with apalutamide.

Current evidence of uncontrolled hypertension, gastrointestinal disorder affecting absorption, active infection (e.g., human immunodeficiency virus [HIV] or viral hepatitis) or other medical condition that would make prednisone/prednisolone (corticosteroid) use contraindicated, chronic medical condition requiring a higher dose of corticosteroid than 10 mg prednisone/prednisolone once daily, any condition that in the opinion of the investigator would preclude participation in this study, patients with baseline severe hepatic impairment (Child Pugh Class C), severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident including transient ischemic attacks), or clinically significant ventricular arrhythmias within 6 months prior to treatment start or New York Heart Association (NYHA) Class II to IV heart disease, seizure or known condition that may pre-dispose to seizure, having partners of childbearing potential and not willing to use a method of birth control deemed acceptable by the principle investigator and chairperson during the study and for 1 week after last study drug administration

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive apalutamide, abiraterone acetate, docetaxel, and prednisone according to a dose-escalation schedule. Docetaxel infusions are administered every 3 weeks, with daily oral administration of other drugs.

6 weeks for initial dose-limiting toxicity assessment

Every 3 weeks for docetaxel infusion

Dose Escalation

Subjects remain at their allocated combination dose until the maximum tolerated dose is determined.

Until maximum tolerated dose is determined

Follow-up

Participants are monitored for safety and effectiveness after treatment, including radiographic progression-free survival and PSA response.

36 months

Images collected at baseline, 12 weeks, and end of study

Treatment Details

Interventions

• Abiraterone acetate
• Apalutamide
• Docetaxel
• Prednisone

Trial Overview This trial tests Apalutamide combined with Abiraterone Acetate, Docetaxel, and Prednisone in men with metastatic castration-resistant prostate cancer (mCRPC). It aims to find the safest dose for Apalutamide when used with these other drugs.

Participant Groups

Group I: All patients Experimental Treatment 4 Interventions

Apalutamide, 120 mg (cohort 1), 240 mg (cohort 2), 180 mg (cohort 3) Abiraterone Acetate 1000mg Prednisone 10mg Docetaxel 75 mg/m2

Abiraterone acetate is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Zytiga for:

• Metastatic castration-resistant prostate cancer

Approved in United States as Zytiga for:

• Metastatic castration-resistant prostate cancer
• High-risk metastatic hormone-sensitive prostate cancer

Approved in Canada as Zytiga for:

• Metastatic castration-resistant prostate cancer

Approved in Japan as Zytiga for:

• Metastatic castration-resistant prostate cancer

Who Is Running the Clinical Trial?

Weill Medical College of Cornell University

Lead Sponsor

Trials

1,103

Recruited

1,157,000+

Janssen Scientific Affairs, LLC

Industry Sponsor

Trials

165

Recruited

579,000+

Ricardo Attar

Janssen Scientific Affairs, LLC

Chief Executive Officer since 2008

PhD in Molecular Biology, University of Buenos Aires

Dr. Anastasia G. Daifotis

Janssen Scientific Affairs, LLC

Chief Medical Officer since 2023

MD

Findings from Research

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 104 patients with metastatic castration-resistant prostate cancer treated with abiraterone acetate, the median overall survival was 16.4 months, highlighting the drug's effectiveness in this patient population.

Key prognostic factors for overall survival included early PSA response (greater than 30% decline at four weeks) and ECOG performance status, suggesting that these metrics can help identify patients who are more likely to benefit from abiraterone acetate treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PSA Kinetics as Prognostic Markers of Overall Survival in Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Abiraterone Acetate. España, S., Ochoa de Olza, M., Sala, N., et al.[2022]

In a phase III study (TITAN) involving men with metastatic castration-sensitive prostate cancer, adding apalutamide to androgen deprivation therapy significantly improved median radiographic progression-free survival and overall survival.

Apalutamide was found to maintain health-related quality of life and had a safety profile similar to that of placebo when combined with androgen deprivation therapy, expanding treatment options for this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Apalutamide: A Review in Metastatic Castration-Sensitive Prostate Cancer. Hoy, SM.[2021]

In the SPARTAN study involving 1207 patients with nonmetastatic castration-resistant prostate cancer, apalutamide significantly improved health-related quality of life (HRQoL) compared to placebo, with patients maintaining better scores over time.

Patients receiving apalutamide experienced minimal side effects and reported no worsening of fatigue, while those on placebo showed a decline in quality of life after about one year, highlighting the efficacy and tolerability of apalutamide in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-related Quality of Life at the SPARTAN Final Analysis of Apalutamide for Nonmetastatic Castration-resistant Prostate Cancer Patients Receiving Androgen Deprivation Therapy. Oudard, S., Hadaschik, B., Saad, F., 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]

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]

Abiraterone acetate (Zytiga®) is an effective antiandrogen for prostate cancer but has poor oral bioavailability (<10%) and requires patients to fast around its administration due to a significant food effect (5-10-fold increase in absorption).

The review highlights the need for improved oral formulation strategies to enhance solubility and bioavailability of abiraterone acetate, aiming to reduce the required dose and eliminate the food effect, which could lead to better patient compliance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral formulation strategies to improve the bioavailability and mitigate the food effect of abiraterone acetate. Schultz, HB., Meola, TR., Thomas, N., et al.[2020]

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]

Abiraterone acetate, in combination with prednisone, received full FDA approval for treating metastatic castration-resistant prostate cancer (mCRPC) based on the COU-AA-302 trial, which involved 1,088 patients and showed a significant improvement in radiographic progression-free survival (rPFS) compared to placebo (8.3 months vs. not reached).

The trial also indicated a favorable trend in overall survival (OS) for patients receiving abiraterone acetate, although it did not reach statistical significance, confirming the drug's efficacy and safety profile consistent with previous studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abiraterone acetate in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer: U.S. Food and Drug Administration drug approval summary. Kluetz, PG., Ning, YM., Maher, VE., et al.[2018]

In a study of 12 men with metastatic castrate-resistant prostate cancer (mCRPC) who were re-treated with abiraterone acetate (AA), only 46% of those who initially responded to AA showed a similar response upon re-treatment, indicating limited efficacy.

The median duration of response to AA re-treatment was short, with a median biochemical progression-free survival of just 2.3 months, suggesting that re-challenging with AA may not provide significant long-term benefits for most patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retreatment of men with metastatic castrate-resistant prostate cancer with abiraterone. Leibowitz-Amit, R., Alimohamed, N., Vera-Badillo, FE., et al.[2016]

References

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

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

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

PSA Kinetics as Prognostic Markers of Overall Survival in Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Abiraterone Acetate. [2022]

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

Apalutamide: A Review in Metastatic Castration-Sensitive Prostate Cancer. [2021]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Health-related Quality of Life at the SPARTAN Final Analysis of Apalutamide for Nonmetastatic Castration-resistant Prostate Cancer Patients Receiving Androgen Deprivation Therapy. [2022]

5. 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]

6. 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]

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

Oral formulation strategies to improve the bioavailability and mitigate the food effect of abiraterone acetate. [2020]

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

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

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

Abiraterone acetate in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer: U.S. Food and Drug Administration drug approval summary. [2018]

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

Retreatment of men with metastatic castrate-resistant prostate cancer with abiraterone. [2016]