Androgen Ablation + Niraparib for Prostate Cancer

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must be taking: Androgen ablation therapy

Must not be taking: PARP inhibitors

Disqualifiers: Metastatic disease, MDS/AML, 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: 21

200 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies the effect of androgen ablation therapy with or without niraparib after standard of care radiation therapy in treating patients with prostate cancer that has not spread to other parts of the body (localized) or that has spread to nearby tissue or lymph nodes (locally advanced). Androgen ablation therapy (also known as hormone therapy) lowers the levels of male hormones called androgens in the body. Androgens stimulate prostate cancer cells to grow. There are 2 types of androgen ablation therapy given in this study: AAP + ADT and Apa + ADT. AAP + ADT is the treatment combination of the drugs abiraterone acetate and prednisone (AAP) given with androgen deprivation therapy (ADT, also known as androgen deprivation therapy or androgen suppression medication, which is used as standard of care to lower testosterone levels in men with high risk localized or metastatic prostate cancer). Apa + ADT is the treatment combination of the drug apalutamide (Apa) given with ADT. Androgen ablation therapy with or without niraparib after radiation therapy may help to control the disease in patients with prostate cancer.

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

The trial protocol does not specify if you need to stop taking your current medications. However, medications that lower the seizure threshold must be stopped or changed at least 4 weeks before joining the study. Also, avoid certain medications that interact with abiraterone acetate.

What data supports the effectiveness of the drug combination used in the Androgen Ablation + Niraparib for Prostate Cancer trial?

Research shows that abiraterone acetate combined with prednisone improves survival in men with metastatic prostate cancer, both when the cancer is sensitive to hormone therapy and when it is resistant. This suggests that the combination of these drugs can be effective in managing prostate cancer. ^{1 2 3 4 5}

Is the combination of androgen ablation and niraparib safe for humans?

The combination of niraparib with abiraterone acetate and prednisone has been studied in patients with prostate cancer, showing a manageable safety profile, meaning that while there may be side effects, they are generally considered acceptable and can be managed. ^{1 6 7 8 9}

How is the drug combination of Androgen Ablation + Niraparib with Abiraterone Acetate, Apalutamide, and Prednisone unique for prostate cancer?

This treatment is unique because it combines androgen ablation (reducing male hormones) with niraparib, a drug that targets DNA repair in cancer cells, alongside abiraterone acetate, apalutamide, and prednisone, which are used to block hormone production and reduce inflammation. This combination aims to tackle prostate cancer from multiple angles, potentially offering benefits over standard treatments that focus on just one mechanism. ^{2 3 7 10 11}

Research Team

Patrick G. Pilie

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

Men over 18 with high-risk localized or locally advanced prostate cancer, who haven't had systemic treatment for it (except ADT within 3 months), can join. They need normal blood counts and organ function, agree to use birth control, and be able to take oral meds. Those with prior major surgery for prostate cancer or certain medical conditions are excluded.

Inclusion Criteria

Willing and able to comply with the protocol for the duration of the study

Patients who have partners of childbearing potential must use birth control methods

My prostate cancer has been confirmed by lab tests.

Exclusion Criteria

Incarcerated or compulsorily detained subjects

I have no lasting side effects from past cancer treatments.

I have a condition that can cause seizures.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Phase

Patients receive apalutamide and physician's choice ADT for up to 3 cycles

12 weeks

3 visits (in-person)

Radiation Phase

Patients undergo radiation therapy and continue apalutamide and ADT for up to 3 cycles

12 weeks

3 visits (in-person)

Adjuvant Phase

Patients continue treatment with apalutamide and ADT, or are randomized to receive additional abiraterone acetate, prednisone, and niraparib for up to 12 cycles

48 weeks

12 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Every 3 months

Treatment Details

Interventions

• Abiraterone Acetate
• Apalutamide
• Niraparib
• Prednisone

Trial Overview The trial is testing if adding the drug Niraparib to standard hormone therapy after radiation helps control prostate cancer better than hormone therapy alone. Participants will receive either AAP + ADT or Apa + ADT hormone therapies along with radiation, then possibly Niraparib.

Participant Groups

Group I: Group B (Apa, ADT, XRT, AAP, niraparib) Experimental Treatment 7 Interventions

PART 1 NEOADJUVANT PHASE (CYCLES 1-3): Patients receive PO QD on days 1-28, and physician's choice ADT. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. PART 2 RADIATION PHASE (CYCLES 4-6): Within 30 days of completing Part 1, patients undergo radiation therapy. Patients also receive apalutamide PO QD on days 1-28 and physician's choice ADT. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. PART 3 ADJUVANT PHASE (CYCLES 7 AND BEYOND): Patients receive abiraterone acetate PO QD, prednisone PO BID, physician's choice ADT, and niraparib PO QD. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

Group II: Group A (Apa, ADT, XRT) Active Control 4 Interventions

PART 1 NEOADJUVANT PHASE (CYCLES 1-3): Patients receive PO QD on days 1-28, and physician's choice ADT. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. PART 2 RADIATION PHASE (CYCLES 4-6): Within 30 days of completing Part 1, patients undergo radiation therapy. Patients also receive apalutamide PO QD on days 1-28 and physician's choice ADT. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. PART 3 ADJUVANT PHASE (CYCLES 7 AND BEYOND): Patients receive apalutamide PO QD on days 1-28 and physician's choice ADT. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable 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+

Findings from Research

In a study of 1199 men with metastatic castration-sensitive prostate cancer, treatment with abiraterone acetate plus prednisone (AA+P) significantly improved overall survival (OS) and radiographic progression-free survival (rPFS) compared to placebo, particularly in patients with lung metastases.

Patients with visceral metastases (VM) who received AA+P had a median OS of 55.4 months versus 33.0 months for those on placebo, and a median rPFS of 30.7 months compared to 18.3 months, indicating that AA+P is an effective treatment option for this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of abiraterone acetate plus prednisone in patients with castration-sensitive prostate cancer and visceral metastases over four years of follow-up: A post-hoc exploratory analysis of the LATITUDE study. Baciarello, G., Özgüroğlu, M., Mundle, S., et al.[2022]

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 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 study of 93 men with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA), the median survival was significantly longer for chemotherapy-naive patients (36.4 months) compared to those previously treated with chemotherapy (13.4 months).

The safety profile of AA was consistent with previous clinical trials, showing low rates of adverse events like hypokalemia and hypertension, suggesting that less intensive monitoring may be appropriate for patients without these complications after 7.5 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abiraterone in metastatic castration-resistant prostate cancer: Efficacy and safety in unselected patients. Marret, G., Doucet, L., Hennequin, C., et al.[2019]

In a study of 87 patients with metastatic castration-resistant prostate cancer (mCRPC), prior treatment with second-line nonsteroidal antiandrogens (NSAA) did not significantly affect the efficacy of abiraterone acetate, as measured by various survival metrics.

The results indicated that both groups (those with prior NSAA treatment and those without) had similar outcomes in terms of prostate-specific antigen progression-free survival and overall survival, suggesting that switching to a second-line NSAA does not hinder the effectiveness of subsequent abiraterone treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prior switching to a second-line nonsteroidal antiandrogen does not impact the therapeutic efficacy of abiraterone acetate in patients with metastatic castration-resistant prostate cancer: a real-world retrospective study. Zhao, JG., Liu, JD., Shen, PF., et al.[2019]

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]

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]

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]

Abiraterone acetate (AA) combined with prednisone significantly improves treatment outcomes in Asian patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC), showing longer median PSA progression-free survival (10.3 months vs. 3.0 months) and overall survival (23.3 months vs. 17.5 months) compared to prednisone alone.

The treatment was generally safe, with no serious adverse events leading to therapy discontinuation, and the most common side effect was elevated liver enzymes, occurring similarly in both treatment groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abiraterone acetate for chemotherapy-naive metastatic castration-resistant prostate cancer: a single-centre prospective study of efficacy, safety, and prognostic factors. Fan, L., Dong, B., Chi, C., et al.[2019]

In a study of 254 metastatic castration-resistant prostate cancer patients treated with abiraterone acetate plus prednisone (AA+P) over a median follow-up of 67.1 weeks, patient-reported outcomes (PROs) showed no significant decline in quality of life or cognitive function, indicating that the treatment is well-tolerated.

The study also reported a 66.4% response rate in prostate-specific antigen (PSA) levels, demonstrating the efficacy of AA+P in managing this patient population while maintaining their overall well-being.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world evidence in patient-reported outcomes (PROs) of metastatic castrate-resistant prostate cancer (mCRPC) patients treated with abiraterone acetate + prednisone (AA+P) across Canada: Final results of COSMiC. Gotto, G., Drachenberg, DE., Chin, J., et al.[2020]

In a study of 60 men with metastatic castration-resistant prostate cancer, switching abiraterone acetate (AA) administration from without food to with food resulted in a 16% PSA decline in those who had rising PSA levels, suggesting potential benefits of this administration change.

Patients who switched to taking AA with food experienced nearly 100 additional days on therapy without an increase in adverse events, indicating that this method may enhance treatment duration and tolerability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reversal of PSA progression on abiraterone acetate through the administration with food in men with metastatic castration-resistant prostate cancer. Stover, JT., Moore, RA., Davis, K., et al.[2018]

References

1. England pubmed.ncbi.nlm.nih.gov

Impact of abiraterone acetate plus prednisone in patients with castration-sensitive prostate cancer and visceral metastases over four years of follow-up: A post-hoc exploratory analysis of the LATITUDE study. [2022]

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

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

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

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

4. England pubmed.ncbi.nlm.nih.gov

Abiraterone in metastatic castration-resistant prostate cancer: Efficacy and safety in unselected patients. [2019]

5. China pubmed.ncbi.nlm.nih.gov

Prior switching to a second-line nonsteroidal antiandrogen does not impact the therapeutic efficacy of abiraterone acetate in patients with metastatic castration-resistant prostate cancer: a real-world retrospective study. [2019]

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 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]

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. England pubmed.ncbi.nlm.nih.gov

Abiraterone acetate for chemotherapy-naive metastatic castration-resistant prostate cancer: a single-centre prospective study of efficacy, safety, and prognostic factors. [2019]

10. Canada pubmed.ncbi.nlm.nih.gov

Real-world evidence in patient-reported outcomes (PROs) of metastatic castrate-resistant prostate cancer (mCRPC) patients treated with abiraterone acetate + prednisone (AA+P) across Canada: Final results of COSMiC. [2020]

11. England pubmed.ncbi.nlm.nih.gov

Reversal of PSA progression on abiraterone acetate through the administration with food in men with metastatic castration-resistant prostate cancer. [2018]