Niraparib + Standard Therapy for Prostate Cancer

(NADIR Trial)

Recruiting at 97 trial locations

Age: 18+

Sex: Male

Trial Phase: Phase 1 & 2

Sponsor: NRG Oncology

Must not be taking: Anti-androgens, HAART, PARP inhibitors

Disqualifiers: Metastatic disease, Active malignancy, others

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

Compensation: Varies

Number of Visits: Unknown

22 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This is a phase I-II trial to find the safety and activity of adding a new drug (neratinib) to the usual treatment (radiation combined with male hormone deprivation therapy) in lowering the chance of prostate cancer growing or returning. Niraparib is an inhibitor of PARP, an enzyme that helps repair deoxyribonucleic acid (DNA) when it becomes damaged. Blocking PARP may help keep cancer cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy. Adding niraparib to the usual care may lower the chance of prostate cancer growing or returning.

Will I have to stop taking my current medications?

The trial requires a washout period of at least 30 days if you have been taking first-generation anti-androgens like bicalutamide, nilutamide, or flutamide. If you are on highly active antiretroviral therapy (HAART) for HIV, you will not be eligible to participate.

Is the combination of Niraparib and standard therapy safe for prostate cancer treatment?

The studies reviewed focus on the safety of intensity-modulated radiotherapy (IMRT) for prostate cancer, showing that it is generally safe with manageable side effects. However, they do not provide specific safety data on the combination of Niraparib with standard therapy for prostate cancer. ^{1 2 3 4 5}

How is the treatment with Niraparib and standard therapy unique for prostate cancer?

This treatment is unique because it combines Niraparib, a drug that blocks proteins involved in DNA repair, with standard therapies like hormone therapy and advanced radiation techniques. This combination targets prostate cancer cells with specific genetic defects, potentially making the treatment more effective for certain patients. ^{6 7 8 9 10}

What data supports the effectiveness of the treatment Niraparib + Standard Therapy for Prostate Cancer?

Research shows that combining hormone therapy with radiation therapy can improve survival in prostate cancer patients. Specifically, using a gonadotropin-releasing hormone agonist (a type of hormone therapy) with radiation therapy has been shown to improve outcomes in prostate cancer treatment. ^{2 11 12 13 14}

Who Is on the Research Team?

M. D Michaelson

Principal Investigator

NRG Oncology

Are You a Good Fit for This Trial?

This trial is for men with high-risk prostate cancer that hasn't spread elsewhere. Eligible participants have a Gleason score of 7 or higher, PSA levels below certain thresholds, and good organ function. They must not have had prior treatments like radical prostatectomy or systemic therapy for prostate cancer and should be willing to use contraception.

Inclusion Criteria

Gleason 8, PSA < 20 ng/mL, and ≥ T2

Hemoglobin ≥ 9.0 g/dL (within 90 days prior to registration)

Serum total bilirubin ≤ 1.5 x ULN or direct bilirubin ≤ 1 x ULN (Note: in subjects with Gilberts syndrome, if total bilirubin is > 1.5 x ULN, measure direct and indirect bilirubin, and if direct bilirubin is ≤ 1.5 x ULN, subject may be eligible) (within 90 days prior to registration)

Exclusion Criteria

PSA > 150 ng/mL

Definitive clinical or radiologic evidence of metastatic disease

Pathologically positive lymph nodes or nodes > 1.5 cm short axis on CT or MR imaging

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase I Treatment

Patients receive niraparib and GnRH agonist therapy. Niraparib continues for 12 months, and GnRH agonist therapy for 24 months. IMRT begins 8 weeks after starting niraparib and GnRH agonist, lasting 6-9 weeks.

24 months

Regular visits for treatment and monitoring

Phase II Treatment

Patients are randomized to receive either standard GnRH agonist therapy or GnRH agonist with niraparib. IMRT begins 8-28 weeks after starting GnRH agonist, lasting 6-9 weeks.

24 months

Regular visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs every 6 months for 3 years, then annually for 3 years.

6 years

What Are the Treatments Tested in This Trial?

Interventions

• Gonadotrophin Releasing Hormone
• Intensity-Modulated Radiation Therapy
• Niraparib

Trial Overview The study tests the effectiveness of Niraparib (an enzyme blocker) combined with standard radiation and hormonal therapies in preventing the return of high-risk prostate cancer. It's a phase II trial aiming to find the best dose while monitoring side effects.

How Is the Trial Designed?

Group I: Phase II, Arm II (niraparib, GnRH, IMRT) Experimental Treatment 3 Interventions

Patients undergo standard of care GnRH agonist androgen suppression therapy for 24 months and concurrent niraparib PO QD (phase I determined dose level) for the first 12 months. Beginning 8 weeks after starting niraparib, patients undergo standard of care IMRT 5 days per week for about 6-9 weeks depending on type of radiation therapy. Treatment is given in the absence of disease progression or unacceptable toxicity.

Group II: Phase I, Dose Level 3 (niraparib, GnRH, IMRT) Experimental Treatment 3 Interventions

Patients undergo standard of care GnRH agonist androgen suppression therapy for 24 months and concurrent niraparib PO QD\* for the first 12 months. Beginning 8 weeks after starting niraparib, patients undergo standard of care IMRT 5 days per week for about 6-9 weeks depending on type of radiation therapy. Treatment given in the absence of disease progression or unacceptable toxicity. \*Niraparib dose level 3: 200 mg.

Group III: Phase I, Dose Level 2 (niraparib, GnRH, IMRT) Experimental Treatment 3 Interventions

Patients undergo standard of care GnRH agonist androgen suppression therapy for 24 months and concurrent niraparib PO QD\* for the first 12 months. Beginning 8 weeks after starting niraparib, patients undergo standard of care IMRT 5 days per week for about 6-9 weeks depending on type of radiation therapy. Treatment is given in the absence of disease progression or unacceptable toxicity. \*Niraparib dose level 2: 100 mg during IMRT 200 mg otherwise.

Group IV: Phase I, Dose Level 1 (niraparib, GnRH, IMRT) Experimental Treatment 3 Interventions

Patients undergo standard of care GnRH agonist androgen suppression therapy for 24 months and concurrent niraparib PO QD\* for the first 12 months. Beginning 8 weeks after starting niraparib, patients undergo standard of care IMRT 5 days per week for about 6-9 weeks depending on type of radiation therapy. Treatment is given in the absence of disease progression or unacceptable toxicity. \*Niraparib dose level 1: 100 mg.

Group V: Phase II, Arm I (GnRH, IMRT) Active Control 2 Interventions

Patients undergo standard of care GnRH agonist androgen suppression therapy for 24 months. Beginning 8-28 weeks after starting GnRH agonist, patients undergo IMRT 5 days per week for about 6-9 weeks depending on type of radiation therapy. Treatment is given in the absence of disease progression or unacceptable toxicity.

Who Is Running the Clinical Trial?

NRG Oncology

Lead Sponsor

Trials

242

Recruited

105,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study of 318 prostate cancer patients with a median follow-up of 56 months, both radiotherapy combined with GnRHa and radiotherapy combined with bicalutamide showed similar five-year biochemical relapse-free survival rates (85.5% for GnRHa and 88.3% for bicalutamide).

Bicalutamide may be a suitable alternative for patients who prefer to avoid the side effects associated with GnRHa, highlighting the need for further randomized trials to compare these two treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiotherapy Plus GnRH Analogue Versus High Dose Bicalutamide: A Case Control Study. Buwenge, M., Deodato, F., Macchia, G., et al.[2020]

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]

The combination of niraparib, a PARP inhibitor, with Radium-223 was found to be safe for treating metastatic castrate-resistant prostate cancer (mCRPC) in men without known BRCA mutations, with manageable dose-limiting toxicities (DLTs) primarily related to blood cell counts.

In a study of 30 patients, the maximum tolerated dose (MTD) varied based on prior chemotherapy exposure, indicating that personalized dosing may be necessary; further research is needed to explore biomarkers that could predict treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Study of Niraparib in Combination with Radium-223 for the Treatment of Metastatic Castrate-Resistant Prostate Cancer. Quinn, Z., Leiby, B., Sonpavde, G., et al.[2023]

Niraparib, a DNA damage repair inhibitor, significantly increased the sensitivity of four head and neck cancer cell lines to both photon and proton radiotherapy, suggesting it could enhance treatment effectiveness.

The study found that niraparib not only reduced colony formation in some cell lines but also increased the relative biological effectiveness (RBE) of protons compared to photons, indicating a potential advantage of proton therapy when combined with niraparib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Proton and photon radiosensitization effects of niraparib, a PARP-1/-2 inhibitor, on human head and neck cancer cells. Wang, L., Cao, J., Wang, X., et al.[2021]

Citations

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

Combined Androgen Blockade in Localized Prostate Cancer Treated With Definitive Radiation Therapy. [2020]

2. Greece pubmed.ncbi.nlm.nih.gov

Feasibility of simultaneous integrated boost IMRT (SIB-IMRT) for castration-resistant prostate cancer. [2014]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Cardiovascular mortality and duration of androgen deprivation for locally advanced prostate cancer: analysis of RTOG 92-02. [2021]

4. Italy pubmed.ncbi.nlm.nih.gov

[Neoadjuvant combined hormonal therapy and radiotherapy with external beam irradiation in prostatic carcinoma]. [2013]

5. Greece pubmed.ncbi.nlm.nih.gov

Radiotherapy Plus GnRH Analogue Versus High Dose Bicalutamide: A Case Control Study. [2020]

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

Radiation technique and outcomes following moderately hypofractionated treatment of low risk prostate cancer: a secondary analysis of RTOG 0415. [2023]

7. Thailand pubmed.ncbi.nlm.nih.gov

Intensity-modulated radiotherapy combined with endocrine therapy for intermediate and advanced prostate cancer: long-term outcome of Chinese patients. [2019]

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

Intensity modulated radiotherapy for localized prostate cancer: rigid compliance to dose-volume constraints as a warranty of acceptable toxicity? [2022]

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

Toxicity assessment of pelvic intensity-modulated radiotherapy with hypofractionated simultaneous integrated boost to prostate for intermediate- and high-risk prostate cancer. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial. [2023]

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

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

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

Phase I Study of Niraparib in Combination with Radium-223 for the Treatment of Metastatic Castrate-Resistant Prostate Cancer. [2023]

13. England pubmed.ncbi.nlm.nih.gov

Niraparib activates interferon signaling and potentiates anti-PD-1 antibody efficacy in tumor models. [2021]

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

Proton and photon radiosensitization effects of niraparib, a PARP-1/-2 inhibitor, on human head and neck cancer cells. [2021]