PARP Inhibitors for Ovarian Cancer

(4PDQ Trial)

Age: Any Age

Sex: Female

Trial Phase: Academic

Sponsor: University of Saskatchewan

Must be taking: PARP inhibitors

Disqualifiers: Ineligible for PARPi, Refusal HRD testing

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 6-12 weeks

100 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug Niraparib for ovarian cancer?

Niraparib has been shown to increase the time patients live without their cancer getting worse (progression-free survival) in those with recurrent ovarian cancer after platinum-based chemotherapy, regardless of BRCA mutation status. It is also used as maintenance therapy for patients with platinum-sensitive recurrent ovarian cancer, showing clinical activity in these cases. ^{1 2 3 4 5}

Is niraparib safe for humans?

Niraparib, a treatment for ovarian cancer, has been studied for safety, showing that most patients experience some side effects, with serious ones like low blood cell counts and high blood pressure in some cases. Dose adjustments are often needed to manage these side effects, and there is a small risk of developing blood disorders like leukemia. ^{6 7 8 9 10}

How is the drug Niraparib unique in treating ovarian cancer?

Niraparib is unique because it is an oral PARP inhibitor that can be used as maintenance therapy for ovarian cancer patients regardless of their BRCA mutation status, unlike other treatments that often require specific genetic markers. It is also notable for its use in patients who have responded to platinum-based chemotherapy, offering a new option for those with recurrent or newly diagnosed ovarian cancer. ^{1 2 3 11 12}

What is the purpose of this trial?

Patients with ovarian cancer with defective DNA repair mechanisms derive substantial benefit from PARP inhibitor (PARPi) maintenance therapy. Both niraparib and olaparib are effective inhibitors of PARP, which exploit already defective DNA repair mechanisms (e.g., via BRCA mutations), particularly those with homologous recombination deficiency (HRD). These two PARPis have notably different toxicity profiles, with niraparib showing many more severe side effects. In this Ovarian Cancer Canada funded study, we will implement perform HRD testing for ovarian cancer patients in Saskatchewan with response to platinum-based chemotherapy. This information will provide personalized and precision estimates about the amount of benefit that can be expected from taking a PARPi. We will evaluate both treatment outcomes and quality of life in a real-world study setting, to inform future decision-making regarding efficacy, quality of life and cost-effectiveness of PARPi therapy, specifically for niraparib. We hypothesize that for patients who are homologous recombinant proficient (HRP), the median 32.7-month incremental benefit (in delaying cancer progression) from taking a PARPi (niraparib is the only PARPi approved in this setting) will not be seen as being value-add when balanced by the decreased quality of life that accompanies the first 6-12 weeks of therapy. We also hypothesize that for women who are HRP, that PARPi therapy will not be cost-efficient.

Eligibility Criteria

This trial is for ovarian cancer patients in Saskatchewan who've responded to platinum-based chemotherapy and will undergo HRD testing. It's designed to help those with defective DNA repair mechanisms decide if PARPi therapy, specifically niraparib, is beneficial considering its impact on quality of life.

Inclusion Criteria

Able to provide oral consent and complete questionnaires in English as per study protocol

I have advanced ovarian cancer.

Exclusion Criteria

I refuse to have HRD testing.

I cannot receive maintenance PARPi therapy.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

HRD Testing

HRD testing is performed for ovarian cancer patients to determine eligibility for PARPi therapy

2 weeks

Treatment

Participants receive PARPi therapy, with a focus on evaluating treatment outcomes and quality of life

6-12 weeks

Follow-up

Participants are monitored for safety, effectiveness, and quality of life after treatment

6 months

Treatment Details

Interventions

• Niraparib

Trial Overview The study tests the effectiveness of a decision aid for using PARP inhibitors (PARPi) like niraparib or olaparib in ovarian cancer patients with homologous recombination deficiency (HRD). It aims to balance treatment benefits against side effects and decreased quality of life during initial weeks.

Participant Groups

Group I: HRD Tested Experimental Treatment 1 Intervention

HRP patients are given a decision aid, while HRD patients are not given a decision.

Who Is Running the Clinical Trial?

University of Saskatchewan

Lead Sponsor

Trials

261

Recruited

156,000+

Findings from Research

Niraparib is the first PARP inhibitor approved for ovarian cancer treatment in patients without BRCA mutations, showing good tolerability and manageable hematologic side effects, especially with new dose modification guidelines.

Current research is exploring niraparib's effectiveness as a maintenance therapy after platinum-based chemotherapy and in recurrent high-grade serous ovarian cancer, highlighting the need for better biomarkers to identify which patients will benefit most from this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib for the treatment of ovarian cancer. Essel, KG., Moore, KN.[2019]

In a real-world study of 22 ovarian cancer patients treated with niraparib at a dose of 200 mg/day, the objective response rate was 33.3%, indicating promising efficacy, especially in patients with homologous recombination deficiency (HRD).

The most common adverse events included nausea, thrombocytopenia, and anemia, with severe thrombocytopenia managed through dose adjustments, suggesting that niraparib can be tolerated with appropriate monitoring and management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of niraparib for ovarian cancer: a single-center observational study from China. Ni, J., Cheng, X., Zhao, Q., et al.[2021]

In a phase 3 trial involving 553 patients with platinum-sensitive, recurrent ovarian cancer, niraparib significantly improved progression-free survival compared to placebo, with median durations of 21.0 months versus 5.5 months for patients with gBRCA mutations, and 12.9 months versus 3.8 months for those with homologous recombination deficiency.

While niraparib was effective, it was associated with moderate bone marrow toxicity, with common grade 3 or 4 adverse events including thrombocytopenia (33.8%), anemia (25.3%), and neutropenia (19.6%), which were managed through dose adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. Mirza, MR., Monk, BJ., Herrstedt, J., et al.[2022]

Niraparib significantly prolongs progression-free survival (PFS) in patients with platinum-sensitive recurrent ovarian cancer, with a median PFS of 18.3 months compared to 5.4 months for placebo, indicating a 68% reduction in the risk of disease progression or death.

The treatment was generally safe, though 50.8% of patients experienced grade ≥3 adverse events, with the most common being decreased neutrophil count and anemia, highlighting the importance of monitoring for side effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer using an individualized starting dose (NORA): a randomized, double-blind, placebo-controlled phase III trial☆. Wu, XH., Zhu, JQ., Yin, RT., et al.[2021]

In a phase 3 trial involving 733 patients with newly diagnosed advanced ovarian cancer, niraparib significantly improved progression-free survival compared to placebo, with a median of 21.9 months versus 10.4 months for patients with homologous-recombination deficiency.

Niraparib also demonstrated a notable overall survival rate of 84% at 24 months, with manageable side effects, including anemia and thrombocytopenia, but no treatment-related deaths, indicating its safety and efficacy as a treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. González-Martín, A., Pothuri, B., Vergote, I., et al.[2019]

Niraparib, a treatment for recurrent ovarian cancer, has a high dose reduction rate of 68.9% due to treatment-emergent adverse events, with thrombocytopenia being a notable cause for 3.3% of patients.

Baseline body weight and platelet count are significant predictors for the risk of severe thrombocytopenia, suggesting that patients with a body weight under 77 kg or platelet count below 150,000/µl may benefit from starting at a lower dose of 200 mg/day without compromising progression-free survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and dose modification for patients receiving niraparib. Berek, JS., Matulonis, UA., Peen, U., et al.[2021]

Niraparib is the first FDA- and EMA-approved PARP inhibitor for maintenance therapy in platinum-sensitive ovarian cancer, effective regardless of BRCA status in first-line treatment.

The review highlights niraparib's pharmacological properties and summarizes efficacy and safety data from key trials, indicating its significant role in improving treatment outcomes for ovarian cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib and Advanced Ovarian Cancer: A Beacon in the Non-BRCA Mutated Setting. Maiorano, MFP., Maiorano, BA., Biancofiore, A., et al.[2023]

Niraparib, a PARP inhibitor, significantly improves progression-free survival in patients with advanced epithelial ovarian cancer, but nearly all patients (≥99%) experience treatment-emergent adverse events, with 51-74% experiencing severe (grade ≥3) events.

An individualized starting dose of niraparib based on body weight and platelet count leads to fewer severe adverse events and dose modifications, suggesting a tailored approach can enhance safety while maintaining treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and management of niraparib monotherapy in ovarian cancer clinical trials. Monk, BJ., González-Martin, A., Buckley, L., et al.[2023]

Niraparib is an FDA and EMA-approved oral PARP inhibitor for maintenance treatment in women with recurrent ovarian cancer who have responded to platinum-based chemotherapy, showing efficacy in both BRCA mutated and wild-type cancers.

While niraparib is effective, it can cause significant hematologic toxicities, such as thrombocytopenia and anemia, necessitating dose adjustments for certain patients to minimize these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The poly (ADP ribose) polymerase inhibitor niraparib: Management of toxicities. Moore, KN., Mirza, MR., Matulonis, UA.[2019]

Niraparib, a PARP inhibitor for recurrent ovarian cancer, showed no significant changes in its pharmacokinetics when taken with a high-fat meal compared to fasting, indicating it can be safely taken with or without food.

The study demonstrated that niraparib was well-tolerated and had similar adverse events regardless of the meal condition, confirming its safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of food on the pharmacokinetics of niraparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, in patients with recurrent ovarian cancer. Moore, K., Zhang, ZY., Agarwal, S., et al.[2019]

Niraparib, a PARP inhibitor, has been shown to be safe for long-term use in patients with recurrent ovarian cancer, with a significant reduction in treatment-emergent adverse events (TEAEs) over time, particularly in the first month of treatment.

The study highlighted the importance of dose adjustments, as the incidence of severe side effects like thrombocytopenia decreased significantly after the initial month, indicating that careful management can enhance the safety of niraparib therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term safety in patients with recurrent ovarian cancer treated with niraparib versus placebo: Results from the phase III ENGOT-OV16/NOVA trial. Mirza, MR., Benigno, B., Dørum, A., et al.[2021]

Niraparib, a PARP inhibitor used for ovarian cancer maintenance therapy, is associated with grade 3/4 thrombocytopenia, particularly in patients with renal insufficiency (CrCl <60 mL/min) and low albumin levels (<3.5 g/dL).

In vitro studies confirmed a direct concentration-dependent relationship between niraparib and platelet toxicity, indicating that higher drug concentrations can lead to more significant decreases in platelet counts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identifying the need to refine the potential patient risk factors for niraparib-induced thrombocytopenia. Smith, JA., Le, T., Martin, GA., et al.[2019]

References

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

Niraparib for the treatment of ovarian cancer. [2019]

2. England pubmed.ncbi.nlm.nih.gov

The efficacy and safety of niraparib for ovarian cancer: a single-center observational study from China. [2021]

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

Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. [2022]

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

Niraparib maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer using an individualized starting dose (NORA): a randomized, double-blind, placebo-controlled phase III trial&#9734;. [2021]

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

Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. [2019]

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

Safety and dose modification for patients receiving niraparib. [2021]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Niraparib and Advanced Ovarian Cancer: A Beacon in the Non-BRCA Mutated Setting. [2023]

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

Safety and management of niraparib monotherapy in ovarian cancer clinical trials. [2023]

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

The poly (ADP ribose) polymerase inhibitor niraparib: Management of toxicities. [2019]

10. Germany pubmed.ncbi.nlm.nih.gov

The effect of food on the pharmacokinetics of niraparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, in patients with recurrent ovarian cancer. [2019]

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

Long-term safety in patients with recurrent ovarian cancer treated with niraparib versus placebo: Results from the phase III ENGOT-OV16/NOVA trial. [2021]

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

Identifying the need to refine the potential patient risk factors for niraparib-induced thrombocytopenia. [2019]