Niraparib + Abiraterone Acetate + Prednisone for Prostate Cancer

(HARMONY Trial)

Overseen By Ahran Lee

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: Qian Qin

Must not be taking: Second generation ARIs, Chemotherapy

Disqualifiers: Neuroendocrine features, Brain metastases, 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: Unknown

64 Participants Needed

Trial Summary

What is the purpose of this trial?

This is an open label, phase II trial in subjects with treatment naïve, metastatic hormone sensitive prostate cancer (mHSPC) with deleterious homologous recombination repair (HRR) alteration(s). These include pathologic alterations in BRCA 1/2, BRIP1, CHEK2, FANCA, PALB2, RAD51B, and/or RAD54L. A total of 64 people will be enrolled to the study.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop your current medications, but it does allow short-term use of corticosteroids and requires that long-term use of certain corticosteroids be avoided. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination of Niraparib, Abiraterone Acetate, and Prednisone for prostate cancer?

Research shows that Abiraterone Acetate combined with Prednisone improves survival in men with metastatic castration-resistant prostate cancer, suggesting potential benefits when used with other drugs like Niraparib. ^{1 2 3 4 5}

Is the combination of Niraparib, Abiraterone Acetate, and Prednisone safe for humans?

The combination of Niraparib with Abiraterone Acetate and Prednisone has been studied in patients with prostate cancer and is generally considered to have a manageable safety profile. Abiraterone Acetate with Prednisone is well tolerated, though it can cause known side effects like liver issues and effects related to hormone changes. Niraparib has been shown to be safe when used with these drugs in prostate cancer patients. ^{6 7 8 9 10}

How is the drug combination of Niraparib, Abiraterone Acetate, and Prednisone unique for prostate cancer?

This drug combination is unique because it combines Niraparib, a PARP inhibitor (a type of drug that blocks certain enzymes involved in repairing damaged DNA), with Abiraterone Acetate and Prednisone, which are already used to treat prostate cancer by blocking androgen production. This combination may offer a novel approach by targeting cancer cells in multiple ways, potentially improving treatment outcomes. ^{1 4 11 12 13}

Research Team

Qian Qin, MD

Principal Investigator

UT Southwestern Comprehensive Cancer Center

Eligibility Criteria

This trial is for men aged 18+ with newly diagnosed metastatic hormone-sensitive prostate cancer and specific genetic alterations (like BRCA1/2, PALB2). Participants must have minimal prior treatment, adequate organ function, and an ECOG Performance Status of ≤ 2. It's open to Hispanic/Latino or non-Hispanic black individuals.

Inclusion Criteria

I have signed the consent form and agreed to share my health information.

I identify as Hispanic/Latino or non-Hispanic black.

My prostate cancer was confirmed through a tissue examination.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Initial Treatment

Participants receive ADT with a GnRH agonist or antagonist, 200 mg niraparib, 1,000 mg abiraterone acetate, and 5 mg prednisone daily for 24 weeks (6 cycles) unless there is progression or unacceptable toxicity.

24 weeks

Cohort B Treatment Extension

Participants with PSA ≤ 4 ng/mL without progression continue ADT + niraparib/abiraterone acetate plus prednisone for 1 year unless progression or unacceptable toxicity.

1 year

Cohort A Treatment Extension

Participants with PSA > 4 ng/mL without progression have the option to continue ADT + niraparib/abiraterone acetate plus prednisone for 2 years or switch to ADT, abiraterone acetate plus prednisone, and docetaxel for 6 doses.

2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

4 years

Treatment Details

Interventions

• Abiraterone Acetate
• Niraparib
• Prednisone

Trial Overview The study tests Niraparib combined with Abiraterone Acetate and Prednisone in patients who haven't had extensive previous treatments. The goal is to see how well this combination works on prostate cancer with certain genetic changes related to DNA repair.

Participant Groups

Group I: Initial Treatment (Cycle 1 to Cycle 6) Experimental Treatment 3 Interventions

Androgen Deprivation Therapy (ADT) with a GnRH agonist or antagonist per standard of care. 200 mg niraparib and 1,000 mg abiraterone acetate dual action tablet (DAT, Akeega) once daily, with 5mg prednisone once daily for 24 weeks (6 cycles) unless there is progression or unacceptable toxicity. After 6 cycles, disease evaluation performed.

Group II: Cohort B: PSA ≤ 4 ng/mL without progression at the completion of 24 weeks Experimental Treatment 3 Interventions

Continue ADT + niraparib/abiraterone acetate plus prednisone for 1 year unless progression or unacceptable toxicity. At 1 year, disease evaluation will occur. * PSA ≥ 0.2 ng/mL: ADT + niraparib/abiraterone acetate plus prednisone will continue for 2 years or until progression or unacceptable toxicity. Therapy beyond 2 years will be per standard of care per investigator discretion. * PSA \< 0.2 ng/mL and PSA not trending up: 1. Continue ADT + niraparib/abiraterone acetate plus prednisone for 2 years or until progression or unacceptable toxicity. Therapy beyond 2 years will be per standard of care per investigator discretion OR 2. STOP ADT + niraparib/abiraterone acetate plus prednisone only IF: * C14 PSA \< 0.2 AND not trending up * Subjects not eligible that elect to stop ADT + niraparib/abiraterone acetate plus prednisone, will be removed from protocol treatment and move to follow-up. Subsequent therapy re-initiation will be at the discretion per standard of care.

Group III: Cohort A: prostate specific antigen (PSA) >4 ng/mL without progression at the completion of 24 weeks Experimental Treatment 5 Interventions

After 6 cycles, there will be an option to: 1. Continue ADT + niraparib/abiraterone acetate plus prednisone in 28-day cycles for a total of 2 years OR until disease progression or unacceptable toxicity. Subsequent therapy will be at the discretion of the investigator per standard of care. 2. Discontinue niraparib. Continue ADT, start abiraterone acetate plus prednisone and docetaxel 75mg/m2 in 21-day cycles. Docetaxel every 3 weeks x 6 doses. At the completion of docetaxel, the subject will move to follow-up per protocol. Niraparib should not be restarted at the completion of docetaxel. Subsequent therapy will be at the discretion of the investigator per standard of care.

Who Is Running the Clinical Trial?

Qian Qin

Lead Sponsor

Trials

2

Recruited

130+

UT Southwestern Comprehensive Cancer Center

Collaborator

Trials

1

Recruited

60+

Janssen, LP

Industry Sponsor

Trials

169

Recruited

329,000+

Founded

1953

Headquarters

Beerse, Belgium

Known For

Mental Health Therapies

Top Products

Imodium, Remicade, Invega, Procrit

Joaquin Duato

Janssen, LP

Chief Executive Officer since 2022

MBA from ESADE Business School

Biljana Naumovic

Janssen, LP

Chief Medical Officer since 2023

MD from Belgrade University Medical School

Findings from Research

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 of 133 patients with non-metastatic castration-resistant prostate cancer, abiraterone acetate (AA) plus prednisone showed comparable overall survival and cancer-specific survival to enzalutamide (Enz) over a median follow-up of 36 months.

However, patients treated with AA plus prednisone had a significantly higher risk of non-cancer-caused death compared to those treated with Enz, suggesting that while both treatments are effective, AA plus prednisone may pose additional safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world survival outcome comparing abiraterone acetate plus prednisone and enzalutamide for nonmetastatic castration-resistant prostate cancer. Tsujino, T., Tokushige, S., Komura, K., et al.[2023]

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]

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 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]

Niraparib at a dose of 200 mg/day was determined to be the recommended phase 2 dose when combined with abiraterone acetate plus prednisone (AAP) for patients with metastatic castration-resistant prostate cancer (mCRPC), as it showed a tolerable safety profile with no new safety signals.

The combination of niraparib with apalutamide resulted in a higher incidence of dose-limiting toxicities, leading to the decision not to further evaluate this combination, highlighting the importance of monitoring drug interactions in treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib with androgen receptor-axis-targeted therapy in patients with metastatic castration-resistant prostate cancer: safety and pharmacokinetic results from a phase 1b study (BEDIVERE). Saad, F., Chi, KN., Shore, ND., et al.[2021]

Abiraterone acetate (AA) combined with prednisone shows favorable safety and efficacy outcomes in treating metastatic prostate cancer, particularly in patients who are asymptomatic or have mild symptoms.

The treatment is generally well tolerated, but it is important to be aware of its known toxicity profile, including mineralocorticoid and corticosteroid-related adverse events, as well as hepatotoxicity, which can inform clinical decision-making.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A drug safety evaluation of abiraterone acetate in the treatment of prostate cancer. Castellan, P., Castellucci, R., Marchioni, M., et al.[2019]

Niraparib (NIRA) is an effective treatment for patients with metastatic castration-resistant prostate cancer who have specific genetic alterations, showing promising results in a Phase II study.

When combined with abiraterone acetate and prednisone, NIRA demonstrated a manageable safety profile while effectively disrupting cancer cell signaling pathways.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib with Abiraterone Acetate and Prednisone for Metastatic Castration-Resistant Prostate Cancer: Phase II QUEST Study Results. Chi, KN., Fleshner, N., Chiuri, VE., et al.[2023]

In the IPATential150 trial involving 1097 patients with metastatic castration-resistant prostate cancer, adding ipatasertib to abiraterone and prednisone significantly improved radiographic progression-free survival for patients with PTEN-loss tumors.

While ipatasertib was associated with a higher rate of serious adverse events and treatment discontinuation compared to placebo, its overall safety profile was considered tolerable, suggesting that with proper management, the side effects could be mitigated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Profile of Ipatasertib Plus Abiraterone vs Placebo Plus Abiraterone in Metastatic Castration-resistant Prostate Cancer. Matsubara, N., de Bono, J., Sweeney, C., 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]

In a study of 131 patients with high-risk, nonmetastatic, castration-resistant prostate cancer, treatment with abiraterone acetate and prednisone resulted in an impressive 86.9% of patients achieving a 50% or greater reduction in prostate-specific antigen (PSA) levels, indicating strong efficacy.

The treatment also showed promising secondary outcomes, with a median time to PSA progression of 28.7 months, while safety was generally acceptable, although 96.2% of patients experienced adverse events, highlighting the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The IMAAGEN Study: Effect of Abiraterone Acetate and Prednisone on Prostate Specific Antigen and Radiographic Disease Progression in Patients with Nonmetastatic Castration Resistant Prostate Cancer. Ryan, CJ., Crawford, ED., Shore, ND., et al.[2021]

In a phase III trial involving men with metastatic castration-resistant prostate cancer (mCRPC), abiraterone acetate combined with prednisone significantly improved overall survival and radiographic progression-free survival compared to placebo.

The incidence of corticosteroid-related adverse events was similar between the treatment and placebo groups, indicating that while monitoring for side effects is necessary, the benefits of improved survival with abiraterone acetate plus prednisone outweigh the risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abiraterone acetate and prednisone in chemotherapy-naïve prostate cancer patients: rationale, evidence and clinical utility. Crawford, ED., Shore, ND., Petrylak, DP., et al.[2020]

In a clinical trial involving 164 men with metastatic castration-resistant prostate cancer, abiraterone acetate combined with prednisone (5 mg twice daily) or dexamethasone (0.5 mg once daily) effectively minimized mineralocorticoid excess, which is important for patient safety.

While abiraterone with dexamethasone showed promising efficacy, it was also linked to adverse metabolic effects, such as increased insulin resistance and decreased bone mineral density, highlighting the need for careful monitoring of these side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of the Safety of Glucocorticoid Regimens in Combination With Abiraterone Acetate for Metastatic Castration-Resistant Prostate Cancer: A Randomized, Open-label Phase 2 Study. Attard, G., Merseburger, AS., Arlt, W., et al.[2022]

References

1. 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]

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

Real-world survival outcome comparing abiraterone acetate plus prednisone and enzalutamide for nonmetastatic castration-resistant prostate cancer. [2023]

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

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

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

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

5. 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]

6. Germany pubmed.ncbi.nlm.nih.gov

Niraparib with androgen receptor-axis-targeted therapy in patients with metastatic castration-resistant prostate cancer: safety and pharmacokinetic results from a phase 1b study (BEDIVERE). [2021]

7. England pubmed.ncbi.nlm.nih.gov

A drug safety evaluation of abiraterone acetate in the treatment of prostate cancer. [2019]

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

Niraparib with Abiraterone Acetate and Prednisone for Metastatic Castration-Resistant Prostate Cancer: Phase II QUEST Study Results. [2023]

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

Safety Profile of Ipatasertib Plus Abiraterone vs Placebo Plus Abiraterone in Metastatic Castration-resistant Prostate Cancer. [2023]

10. 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]

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

The IMAAGEN Study: Effect of Abiraterone Acetate and Prednisone on Prostate Specific Antigen and Radiographic Disease Progression in Patients with Nonmetastatic Castration Resistant Prostate Cancer. [2021]

12. England pubmed.ncbi.nlm.nih.gov

Abiraterone acetate and prednisone in chemotherapy-naïve prostate cancer patients: rationale, evidence and clinical utility. [2020]

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

Assessment of the Safety of Glucocorticoid Regimens in Combination With Abiraterone Acetate for Metastatic Castration-Resistant Prostate Cancer: A Randomized, Open-label Phase 2 Study. [2022]