Report on Niraparib (Zejula®): A Comprehensive Oncological Drug Monograph

Executive Summary

Niraparib, marketed under the brand name Zejula®, is an orally bioavailable, once-daily small-molecule inhibitor of Poly (ADP-ribose) Polymerase (PARP) enzymes, specifically PARP-1 and PARP-2.[1] As a targeted therapy, its primary mechanism of action leverages the principle of synthetic lethality, proving most effective in tumors characterized by Homologous Recombination Deficiency (HRD), a state that includes, but is not limited to, germline or somatic mutations in the

BRCA1 and BRCA2 genes.[4] Niraparib has established a significant role in gynecologic oncology, primarily as a maintenance therapy for adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer following a response to platinum-based chemotherapy, in both the first-line and recurrent settings.[6]

The clinical development of Niraparib is defined by a compelling yet complex narrative. Pivotal clinical trials, most notably the PRIMA and NOVA studies, have consistently demonstrated a statistically significant and clinically meaningful benefit in Progression-Free Survival (PFS).[8] This robust effect on delaying disease progression formed the basis for its initial broad regulatory approvals. However, this efficacy is juxtaposed with a notable toxicity profile, dominated by hematologic adverse events such as thrombocytopenia, anemia, and neutropenia. This safety challenge prompted a paradigm shift in its administration, leading to the development and implementation of an individualized starting dose (ISD) based on patient weight and baseline platelet count to improve tolerability.[11]

Furthermore, the regulatory story of Niraparib is a dynamic one, reflecting the maturation of clinical trial data over time. While initial approvals were expansive, the final analysis of the PRIMA trial in the first-line maintenance setting did not demonstrate a statistically significant benefit in Overall Survival (OS). This long-term finding, likely confounded by the use of subsequent effective therapies in the control arms, led the U.S. Food and Drug Administration (FDA) to re-evaluate the risk-benefit profile and subsequently narrow the first-line indication to the patient population with HRD-positive tumors, where the benefit is most pronounced.[13]

This report provides an exhaustive, expert-level monograph on Niraparib. It synthesizes the full spectrum of available data, from its fundamental chemical properties and preclinical pharmacology to its complex clinical trial evidence, pharmacokinetic profile, and evolving safety and regulatory landscape. The objective is to deliver a definitive resource that contextualizes Niraparib's current and future role in the oncological therapeutic armamentarium.

Chemical Identity and Pharmaceutical Properties

A precise understanding of a drug's chemical and pharmaceutical properties is foundational to its development, manufacturing, and clinical application. Niraparib is a well-characterized small molecule with specific structural features that are critical to its biological activity.

Nomenclature and Identifiers

Niraparib is known by several names and is cataloged across numerous scientific and regulatory databases. Its primary development code was MK-4827.[1] The systematic International Union of Pure and Applied Chemistry (IUPAC) name is 2-phenyl]indazole-7-carboxamide, which precisely describes its molecular architecture.[2] The molecule possesses a critical stereocenter at the 3-position of the piperidine ring, with the (S)-configuration being the active enantiomer.[1] This stereochemical specificity underscores the importance of advanced chiral synthesis or separation techniques in its manufacturing process to ensure the purity and potency of the final drug product.[18]

The drug is formulated for clinical use as niraparib tosylate monohydrate, a salt form chosen to optimize physicochemical properties such as solubility and stability, which are essential for consistent oral absorption and bioavailability.[20] The use of a specific salt form is a standard pharmaceutical practice to convert an active pharmaceutical ingredient (API) into a viable drug product. The selection of the tosylate monohydrate form was a deliberate outcome of extensive preclinical formulation development aimed at creating a stable and effective oral medication.

Commercially, Niraparib is marketed globally under the brand name Zejula®.[2] Key identifiers for Niraparib are consolidated in Table 1.

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Table 1: Drug Identification and Chemical Properties of Niraparib

Property	Value	Source Snippet(s)
Drug Name	Niraparib	1
DrugBank ID	DB11793	1
Type	Small Molecule	1
CAS Number (Free Base)	1038915-60-4	1
CAS Number (Tosylate Salt)	1038915-73-9	20
IUPAC Name	2-phenyl]indazole-7-carboxamide	2
Brand Name	Zejula®	2
Chemical Formula (Free Base)	C19​H20​N4​O	1
Molar Mass (Free Base)	320.396 g·mol⁻¹	2
ChEBI ID	CHEBI:176844	1
UNII	HMC2H89N35	1

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Pharmaceutical Formulation

Niraparib is supplied as 100 mg oral capsules.[6] These capsules have a distinctive appearance, with a white body imprinted with "100 mg" in black ink and a purple cap imprinted with "Niraparib" in white ink.[24]

An important aspect of the formulation is the inclusion of the excipient tartrazine, also known as FD&C Yellow No. 5.[11] This coloring agent has been associated with allergic-type reactions, including bronchial asthma, in a small subset of the population. This sensitivity is observed more frequently in individuals who also have an allergy to aspirin. Therefore, the prescribing information includes a caution for use in patients with a known aspirin hypersensitivity, highlighting the need for clinicians to be aware of all formulation components, not just the active ingredient.[11]

Mechanism of Action and Preclinical Pharmacology

Niraparib's efficacy as an antineoplastic agent is rooted in its targeted inhibition of the Poly (ADP-ribose) Polymerase (PARP) family of nuclear enzymes. Its mechanism exploits a specific vulnerability in cancer cells with deficient DNA repair pathways, a concept known as synthetic lethality.

Primary Target: PARP-1 and PARP-2 Inhibition

Niraparib is a potent and highly selective inhibitor of PARP-1 and PARP-2.[1] These two enzymes are central to a DNA repair mechanism called the Base Excision Repair (BER) pathway, which is responsible for identifying and mending single-strand breaks (SSBs) in DNA.[4] SSBs are common, spontaneous lesions that can arise from oxidative damage or other cellular stresses. If left unrepaired, they can stall DNA replication, leading to the collapse of replication forks and the formation of more dangerous double-strand breaks (DSBs).

In vitro enzymatic assays have quantified Niraparib's high affinity for its targets, demonstrating half-maximal inhibitory concentrations (IC50​) of 3.8 nM for PARP-1 and 2.1 nM for PARP-2.[1] Its selectivity for PARP-1 and PARP-2 is over 100 times greater than for other PARP family members, ensuring a focused therapeutic effect and minimizing off-target activity.[27]

The Principle of Synthetic Lethality

The core therapeutic strategy of Niraparib relies on synthetic lethality.[5] This principle describes a genetic interaction where a defect in one of two genes or pathways has no effect on cell viability, but the simultaneous defect of both pathways is lethal.

1. PARP Inhibition Blocks SSB Repair: By inhibiting PARP-1 and PARP-2, Niraparib prevents the efficient repair of SSBs. This leads to an accumulation of these lesions within the cell.[4]
2. Conversion to DSBs: When a cell with accumulated SSBs enters the S phase of the cell cycle to replicate its DNA, the replication machinery encounters these unrepaired breaks. This encounter causes the replication fork to collapse, converting the relatively benign SSBs into highly cytotoxic DSBs.[5]
3. Reliance on Homologous Recombination: Healthy cells, which are Homologous Recombination Proficient (HRp), can effectively repair these DSBs using the high-fidelity Homologous Recombination (HR) repair pathway. This pathway relies on a complex of proteins, including those encoded by the well-known tumor suppressor genes BRCA1 and BRCA2.[4]
4. Synthetic Lethality in HR-Deficient Cells: A significant subset of cancers, particularly high-grade serous ovarian cancer, are characterized by Homologous Recombination Deficiency (HRD). This deficiency can arise from germline or somatic mutations in BRCA1/2 or other HR pathway genes (e.g., PALB2, RAD51C), or from epigenetic mechanisms that silence these genes.[4] In these HRD cells, the primary pathway for repairing DSBs is already compromised. When Niraparib is introduced, it blocks the alternative SSB repair pathway. The cell is thus left with two defective DNA repair mechanisms. The resulting accumulation of unrepaired DSBs leads to overwhelming genomic instability, cell cycle arrest, and ultimately, apoptosis (programmed cell death).[5]

This targeted induction of cell death in cancer cells with a pre-existing HRD, while largely sparing healthy HRp cells, is the essence of Niraparib's synthetic lethal mechanism.

Dual Mechanism of Cytotoxicity

Niraparib's cell-killing effect is driven by two distinct but related actions:

1. Catalytic Inhibition: Niraparib binds to the catalytic domain of the PARP enzyme, preventing it from synthesizing poly(ADP-ribose) chains. This action blocks the recruitment of other DNA repair factors to the site of an SSB, effectively inhibiting the BER pathway.[7]
2. PARP Trapping: Perhaps more importantly, Niraparib's binding to PARP also prevents the enzyme from dissociating from the DNA once it has located a break. This "trapping" of the PARP-DNA complex creates a physical obstruction on the DNA strand.[5] These trapped complexes are highly toxic lesions themselves, as they potently block DNA replication and transcription, leading to the generation of DSBs and cell death. The potency of PARP trapping is considered a key driver of cytotoxicity and may explain the activity of PARP inhibitors even in tumors that are not classically defined as HRD.

Preclinical Evidence of Activity

The therapeutic hypothesis for Niraparib was robustly validated in preclinical studies. In vitro experiments showed that Niraparib induced cytotoxicity and inhibited the proliferation of a range of cancer cell lines, including those with both mutant and wild-type BRCA1/2 genes.[28] This early finding hinted that its efficacy might extend beyond the

BRCA-mutated population. This was confirmed in vivo, where Niraparib monotherapy demonstrated significant tumor growth inhibition in mouse xenograft models of human cancers with BRCA1/2 deficiencies, as well as in human patient-derived xenograft models characterized by a broader HRD status.[28]

Furthermore, preclinical research identified Niraparib as a potent radiosensitizing agent. By inhibiting DNA repair, it enhances the cell-killing effects of radiation, a finding that has prompted clinical investigation of Niraparib in combination with radiotherapy in tumors like glioblastoma and lung cancer.[1]

The efficacy of Niraparib is not limited to tumors with BRCA mutations. The broader concept of HRD encompasses a wider range of genetic and epigenetic alterations that impair the HR pathway. This state can be identified using genomic assays that measure features of "genomic scarring," such as a high genomic instability score (GIS).[32] The clinical development strategy for Niraparib was built upon this understanding, with pivotal trials designed to evaluate its efficacy in patient populations defined not only by

BRCA status but also by this broader HRD biomarker, as well as in patients with HR-proficient tumors. This approach has been central to defining its clinical utility and its approved indications.

Clinical Pharmacokinetics and Metabolism

The pharmacokinetic (PK) profile of a drug describes its absorption, distribution, metabolism, and excretion (ADME). These properties determine the drug's exposure in the body and are fundamental to establishing an effective and safe dosing regimen. Niraparib possesses a favorable PK profile characterized by good oral bioavailability, extensive tissue distribution, a long half-life supporting once-daily dosing, and a metabolic pathway that minimizes the risk of common drug-drug interactions.

Absorption, Distribution, Metabolism, and Excretion (ADME)

• Absorption: Niraparib is well-absorbed after oral administration, with an absolute bioavailability of approximately 73%.[2] Following a single oral dose, it reaches peak plasma concentrations ( Cmax​) in approximately 3 hours.[2] The systemic exposure, as measured by Cmax​ and the area under the concentration-time curve (AUC), increases proportionally with doses from 30 mg to 400 mg. Upon repeated daily dosing, Niraparib accumulates approximately 2-fold, reaching steady-state concentrations after 21 days.[27] The presence of food does not clinically impact its absorption; while a high-fat meal can slightly increase exposure, the effect is not significant enough to warrant dosing restrictions, allowing patients to take it with or without food.[25]
• Distribution: Niraparib is extensively distributed throughout the body, as indicated by its large apparent volume of distribution (Vd​/F) of 1,074 to 1,220 L.[25] In the bloodstream, it is moderately bound (83%) to plasma proteins, primarily albumin.[2]
• Metabolism: The metabolism of Niraparib represents one of its most important clinical characteristics. It is primarily metabolized by carboxylesterases (CEs), a class of hydrolytic enzymes, to form its major, inactive metabolite, M1 (a carboxylic acid).[2] This M1 metabolite can be further metabolized via glucuronidation by UDP-glucuronosyltransferases (UGTs) to form M10.[27] Critically, Niraparib is not a significant substrate, inhibitor, or inducer of the cytochrome P450 (CYP) enzyme system.[2] This metabolic pathway largely insulates it from the many drug-drug interactions (DDIs) associated with the CYP system, a significant advantage for cancer patients who are often receiving multiple concomitant medications.
• Excretion: Niraparib has a long terminal elimination half-life (t1/2​) of approximately 36 to 50 hours, which is consistent with and supports a convenient once-daily dosing schedule.[2] It is eliminated from the body through both renal and fecal routes. Following a single radiolabeled dose, approximately 48% of the dose was recovered in the urine and 39% in the feces over 21 days. Unchanged Niraparib accounted for 11% of the dose in urine and 19% in feces, indicating that both direct excretion of the parent drug and clearance of its metabolites are important elimination pathways.[2] The apparent total clearance (CL/F) in cancer patients is approximately 16 L/h.[27]

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Table 2: Summary of Key Pharmacokinetic Parameters of Niraparib

Parameter	Value	Comment/Context	Source Snippet(s)
Bioavailability	~73%	Good oral absorption.	2
Tmax​ (Time to Peak)	~3 hours	Reaches peak concentration relatively quickly after dosing.	2
Protein Binding	83%	Moderately bound to plasma proteins, mainly albumin.	2
Volume of Distribution (Vd​/F)	1,074 - 1,220 L	Indicates extensive distribution into body tissues.	25
Metabolism Pathway	Primarily Carboxylesterases (CEs); not CYP450-dependent.	Minimizes risk of common pharmacokinetic drug-drug interactions.	2
Elimination Half-life (t1/2​)	36 - 50 hours	Long half-life supports convenient once-daily dosing.	2
Primary Excretion Routes	Urine (~48%) and Feces (~39%)	Elimination occurs via both renal and hepatobiliary pathways.	2

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Population Pharmacokinetics and Dosing Strategy

The initial approval of Niraparib was based on a fixed starting dose (FSD) of 300 mg once daily. However, clinical experience revealed high rates of significant hematologic toxicity, particularly thrombocytopenia, with this regimen.[10] This observation prompted extensive population PK analyses, which pooled data from over 1,400 patients across four major clinical trials (PN001, QUADRA, NOVA, and PRIMA).[12]

These sophisticated modeling studies yielded a crucial finding: a clear exposure-response relationship for toxicity. The analyses demonstrated that higher Niraparib exposure (specifically, the steady-state area under the curve, AUCss​), lower baseline body weight, and lower baseline platelet count were all independent predictors of an increased risk for developing Grade ≥3 thrombocytopenia.[12] In contrast, no consistent exposure-response relationship was observed for efficacy (PFS).[12]

This pharmacometric evidence provided a strong scientific rationale for a paradigm shift in dosing. It was hypothesized that an individualized starting dose (ISD) regimen—using a lower starting dose of 200 mg for patients at higher risk of toxicity (body weight <77 kg or baseline platelet count <150,000/µL)—could reduce the incidence of severe hematologic adverse events without compromising the drug's antitumor efficacy. The PK models predicted that while the initial exposure would be lower in the ISD group, the overall exposure throughout the treatment course would be comparable to the FSD group, primarily because patients on the ISD would require fewer dose reductions and interruptions due to better tolerability.[12]

This PK-driven hypothesis was prospectively incorporated into the design of the PRIMA trial and ultimately validated.[9] The ISD strategy is now the standard of care for first-line maintenance therapy and represents a successful example of translating fundamental pharmacokinetic principles into a safer, more personalized clinical practice to optimize the therapeutic window of a potent drug.

Clinical Development and Efficacy

The clinical utility of Niraparib has been established through a series of large, well-conducted, international Phase 3 trials. These studies have defined its role in the treatment of advanced ovarian cancer, from first-line maintenance to the management of recurrent disease. The data from these trials, particularly the primary analyses of Progression-Free Survival (PFS) and the subsequent long-term analyses of Overall Survival (OS), tell a complex and evolving story about the drug's benefits and limitations.

The PRIMA Trial: First-Line Maintenance Therapy in Advanced Ovarian Cancer

The PRIMA trial (also known as ENGOT-OV26/GOG-3012; NCT02655016) was a landmark study designed to evaluate Niraparib as a first-line maintenance therapy.[38] It was a Phase 3, randomized (2:1), double-blind, placebo-controlled trial that enrolled 733 patients with newly diagnosed, advanced (FIGO Stage III or IV) high-grade ovarian cancer.[9] A key feature of the trial was its inclusion of a high-risk patient population—those with residual disease after surgery or those who received neoadjuvant chemotherapy—who had achieved a complete or partial response (CR/PR) to their initial platinum-based chemotherapy.[39] The primary endpoint was PFS, which was assessed hierarchically, first in the population with Homologous Recombination Deficiency (HRD-positive) and then in the overall population.[33]

Primary Analysis and Initial Approval:

The primary results of PRIMA, published in the New England Journal of Medicine in 2019, were overwhelmingly positive and met the primary endpoint.42

• In the HRD-positive population (n=373), maintenance with Niraparib resulted in a median PFS of 21.9 months, compared to 10.4 months with placebo. This represented a 57% reduction in the risk of disease progression or death (Hazard Ratio 0.43; 95% Confidence Interval [CI], 0.31–0.59; p<0.0001).[33]
• In the overall population (n=733), Niraparib extended the median PFS to 13.8 months versus 8.2 months for placebo, a 38% risk reduction (HR 0.62; 95% CI, 0.50–0.76; p<0.001).[9]

The benefit was observed across all prespecified exploratory subgroups. This included patients with BRCA-mutated tumors (HR 0.40), those with non-BRCA-mutated HRD-positive tumors (HR 0.50), and even those with HR-proficient (HRp) tumors (HR 0.68).[9] These compelling PFS data led to a broad FDA approval in April 2020 for Niraparib as a first-line maintenance treatment for all women with advanced ovarian cancer who had responded to platinum chemotherapy, regardless of their biomarker status.[7]

Long-Term Follow-up and Final Overall Survival Analysis:

While PFS measures the immediate impact of a drug on tumor growth, Overall Survival (OS) is the gold standard for demonstrating long-term clinical benefit. The final OS analysis of the PRIMA trial was presented at the European Society for Medical Oncology (ESMO) Congress in 2024, after a median follow-up of approximately six years.13

• The analysis showed no statistically significant difference in OS between the Niraparib and placebo arms.
• In the overall population, the median OS was 46.6 months for Niraparib versus 48.8 months for placebo (HR 1.01; p=0.8834).[44]
• In the HRD-positive population, the median OS was 71.9 months for Niraparib versus 69.8 months for placebo (HR 0.95).[44]
• Despite the lack of OS benefit, the PFS benefit was sustained with longer follow-up. At 5 years, 22% of patients in the overall population on Niraparib were progression-free compared to 12% on placebo. In the HRD-positive population, this difference was even more pronounced: 35% versus 16%, respectively.[44]

The disconnect between the robust PFS benefit and the neutral OS result is a critical finding. It is widely believed to be confounded by the high rate of effective subsequent therapies, including PARP inhibitors, that patients in the placebo arm received after their disease progressed. This "crossover" effect can mask a true survival benefit of earlier treatment. Nonetheless, this outcome prompted the FDA to narrow the first-line maintenance indication to only include patients with HRD-positive tumors, where the magnitude of the PFS benefit is greatest and the risk-benefit assessment remains most favorable.[14]

The NOVA Trial: Maintenance Therapy in Recurrent Ovarian Cancer

The ENGOT-OV16/NOVA trial (NCT01847274) was the pivotal study that first established Niraparib as a major therapy in ovarian cancer.[46] It was a Phase 3, randomized (2:1), double-blind, placebo-controlled trial that enrolled 553 patients with platinum-sensitive recurrent ovarian cancer who were in a CR or PR to their most recent platinum-based chemotherapy.[10] The trial's innovative design included two independent cohorts based on the results of a germline

BRCA (gBRCA) mutation test: a gBRCA-mutated (gBRCAmut) cohort and a non-gBRCAmut cohort.[10] The primary endpoint was PFS.

Primary Analysis and Landmark Approval:

The primary results, published in the New England Journal of Medicine in 2016, were highly positive and practice-changing.10

• In the gBRCAmut cohort (n=203), patients receiving Niraparib had a median PFS of 21.0 months, a nearly four-fold improvement over the 5.5 months seen with placebo (HR 0.27; 95% CI, 0.17–0.41; p<0.001).[8]
• In the overall non-gBRCAmut cohort (n=350), Niraparib also demonstrated a significant benefit, with a median PFS of 9.3 months versus 3.9 months for placebo (HR 0.45; 95% CI, 0.34–0.61; p<0.001).[8]
• Within the non-gBRCAmut cohort, a prespecified analysis of patients with HRD-positive tumors showed an even greater benefit, with a median PFS of 12.9 months versus 3.8 months (HR 0.38).[10]

These data demonstrated for the first time that a PARP inhibitor could provide significant benefit to patients with recurrent ovarian cancer beyond just the BRCA-mutated population. This led to Niraparib's initial FDA approval in March 2017 for the maintenance treatment of recurrent ovarian cancer, irrespective of BRCA status.[30] Post-hoc analyses further confirmed that the PFS benefit was significant regardless of whether patients had achieved a CR or PR to their prior chemotherapy.[47]

Long-Term Follow-up and Secondary Endpoints:

Similar to PRIMA, the final OS analysis of the NOVA trial, conducted after extensive efforts to retrieve missing data, did not show a statistically significant difference between the treatment arms (gBRCAmut cohort HR 0.85; non-gBRCAmut cohort HR 1.06).48 However, long-term analyses of other important endpoints continued to favor Niraparib. These included time to first subsequent therapy (TFST) and PFS2 (time from randomization to second disease progression), suggesting a persistent treatment effect that delayed the need for subsequent chemotherapy.48 Furthermore, a specialized analysis of Time Without Symptoms or Toxicity (TWiST) showed that Niraparib provided patients with a longer duration of quality time free from disease symptoms and treatment toxicity compared to routine surveillance.49

The QUADRA Trial: Late-Line Treatment for HRD-Positive Cancer

The QUADRA trial (NCT02354586) was a single-arm, open-label Phase 2 study that investigated Niraparib in a heavily pre-treated population of patients with advanced ovarian cancer who had received three or more prior chemotherapy regimens.[32] This study was designed to assess Niraparib's activity as a treatment, rather than as maintenance therapy.

The primary endpoints were Objective Response Rate (ORR) and Duration of Response (DOR).[32] The trial provided key evidence in a specific biomarker-selected population. In the cohort of patients with HRD-positive tumors (defined as having a tumor

BRCA mutation or a genomic instability score ≥42) who were PARP inhibitor-naive, Niraparib demonstrated an ORR of 24% (all partial responses), with a median DOR of 8.3 months.[32] These results showed that Niraparib had meaningful single-agent activity in a late-line setting for patients with a defined molecular vulnerability. This led to an FDA approval in October 2019 for this specific indication, which was linked to the use of an FDA-approved companion diagnostic test.[6] This indication was later voluntarily withdrawn by the manufacturer in 2022 for the non-BRCAm subgroup, as part of an industry-wide re-evaluation of PARP inhibitors in late-line settings.[50]

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Table 3: Overview of Pivotal Clinical Trials for Niraparib

Trial Name (NCT ID)	Phase	Setting	Patient Population	N	Arms	Primary Endpoint	Key PFS Result (HR, p-value)	Key OS Result (HR)	Source Snippet(s)
PRIMA (NCT02655016)	3	First-Line Maintenance	Advanced Ovarian Cancer (High-Risk) with CR/PR to 1L Platinum Chemotherapy	733	Niraparib vs. Placebo (2:1)	PFS	Overall: HR 0.62, p<0.001 HRD+: HR 0.43, p<0.0001	Overall: HR 1.01 (Not Significant)	9
NOVA (NCT01847274)	3	Recurrent Maintenance	Platinum-Sensitive Recurrent Ovarian Cancer with CR/PR to Platinum Chemotherapy	553	Niraparib vs. Placebo (2:1)	PFS	gBRCAmut: HR 0.27, p<0.001 non-gBRCAmut: HR 0.45, p<0.001	gBRCAmut: HR 0.85 (Not Significant)	8
QUADRA (NCT02354586)	2	Late-Line Treatment	Advanced Ovarian Cancer (≥3 prior chemotherapies)	98	Niraparib (single arm)	ORR	N/A (ORR in HRD+ cohort: 24%)	N/A	6

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Regulatory History and Approved Indications

The regulatory journey of Niraparib has been dynamic, reflecting the maturation of clinical evidence over time. Initial approvals were granted based on compelling primary endpoint data, while subsequent long-term follow-up has led to important refinements of its labeled indications. The drug was developed by Tesaro, Inc., which was later acquired by GlaxoSmithKline (GSK), the current marketer.[46]

United States (U.S. Food and Drug Administration - FDA)

Niraparib's path to market in the U.S. was expedited due to the high unmet need in ovarian cancer, receiving Fast Track, Priority Review, and Breakthrough Therapy designations.[30]

• March 27, 2017 (Initial Approval): Based on the robust PFS benefit shown in the NOVA trial, the FDA granted its first approval for Niraparib. The indication was for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. Notably, this approval was for all-comers, regardless of BRCA or HRD status.[24]
• October 23, 2019 (Indication Expansion): Following the results of the QUADRA trial, the FDA approved Niraparib for the treatment (not maintenance) of adult patients with advanced ovarian cancer who have been treated with three or more prior chemotherapy regimens and whose cancer is associated with HRD-positive status. This indication was specifically defined by either a deleterious BRCA mutation or a genomic instability score (GIS) ≥42 and was linked to the use of the Myriad myChoice CDx as a companion diagnostic.[6]
• April 29, 2020 (Major Expansion): Based on the primary analysis of the PRIMA trial, the FDA approved Niraparib for the first-line maintenance treatment of adult patients with advanced ovarian cancer who are in a complete or partial response to first-line platinum-based chemotherapy. Mirroring the recurrent setting, this approval was initially granted for all patients, regardless of biomarker status.[7]
• September 14, 2022 (Partial Withdrawal): GSK voluntarily withdrew the indication for late-line treatment in patients with non-BRCA-mutated, HRD-positive tumors (the GIS ≥42 portion of the QUADRA indication). This was part of a broader industry re-evaluation of the risk-benefit profile of PARP inhibitors in heavily pre-treated populations based on final OS analyses from other trials.[50]
• June 2025 (Indication Narrowing): In a significant regulatory update reflecting the final OS data from the PRIMA trial, the FDA narrowed the first-line maintenance indication. The approval is now restricted to adult patients with advanced ovarian cancer whose cancer is associated with HRD-positive status.[14] This decision aligns the indication with the patient population demonstrating the most substantial and durable benefit, effectively removing the HR-proficient population from the approved first-line maintenance setting.

European Union (European Medicines Agency - EMA)

The EMA's regulatory timeline has followed a similar trajectory, though with some differences in the final labeled indications.

• November 16, 2017 (Initial Approval): The EMA granted its initial marketing authorization for Zejula as a monotherapy for the maintenance treatment of adult patients with platinum-sensitive, relapsed, high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response to platinum-based chemotherapy.[1]
• October 27, 2020 (Indication Expansion): The EMA extended the indication to include the first-line maintenance setting. Zejula was approved as monotherapy for the maintenance treatment of adult patients with advanced (FIGO Stages III and IV) high-grade ovarian, fallopian tube, or primary peritoneal cancer who are in response following completion of first-line platinum-based chemotherapy.[50] As of the latest available information, this European indication remains for all patients, regardless of biomarker status, creating a notable divergence from the more restrictive U.S. label.[29]

This transatlantic difference may be due to varying regulatory review timelines or different interpretations of the risk-benefit balance in the HR-proficient population, where the EMA may place greater emphasis on the significant PFS benefit as a clinically meaningful outcome.

Other Regions

Niraparib has also received approvals in other major jurisdictions, including by Health Canada on June 27, 2019.[1] Additionally, a combination product of Niraparib with abiraterone acetate (Akeega) has been approved in the U.S. and Canada for the treatment of adults with deleterious or suspected deleterious

BRCA-mutated metastatic castration-resistant prostate cancer (mCRPC).[27]

The regulatory history of Niraparib serves as a compelling case study in modern, evidence-based drug regulation. The journey from broad approvals based on strong surrogate endpoints (PFS) to more refined indications based on mature, long-term outcomes (OS) demonstrates a responsive and dynamic system that seeks to continually optimize the clinical use of potent therapies.

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Table 4: Summary of FDA and EMA Regulatory Milestones and Approved Indications

Regulatory Body	Date	Action	Indication	Basis (Trial)	Key Context	Source Snippet(s)
FDA	Mar 2017	Initial Approval	Recurrent Maintenance (All-comers)	NOVA	Approved regardless of BRCA status based on strong PFS benefit.	30
EMA	Nov 2017	Initial Approval	Recurrent Maintenance (Platinum-sensitive, relapsed)	NOVA	Approved for patients in response to platinum chemotherapy.	50
FDA	Oct 2019	Expansion	Late-Line Treatment (HRD-positive)	QUADRA	For patients with ≥3 prior chemotherapies; linked to companion diagnostic.	6
FDA	Apr 2020	Expansion	First-Line Maintenance (All-comers)	PRIMA	Broad approval based on primary PFS analysis showing benefit for all.	7
EMA	Oct 2020	Expansion	First-Line Maintenance (Advanced, high-grade)	PRIMA	Broad approval for patients in response to 1L platinum chemotherapy.	50
FDA	Sep 2022	Partial Withdrawal	Late-Line Treatment (non-BRCAm HRD+)	QUADRA	Voluntary withdrawal of the non-BRCAm portion of the late-line indication.	50
FDA	Jun 2025	Narrowing	First-Line Maintenance (HRD-positive only)	PRIMA (Final OS)	Indication restricted based on final OS data showing lack of benefit in HRp group.	14

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Safety Profile, Tolerability, and Risk Management

While Niraparib offers significant efficacy, its use is associated with a well-defined and substantial toxicity profile that requires diligent monitoring and proactive management. The safety data, pooled from large clinical trials involving thousands of patients, are dominated by hematologic adverse reactions, which are considered on-target effects stemming from the drug's mechanism of action.

Common Adverse Reactions

The most frequently reported adverse reactions (occurring in ≥10% of patients) across pivotal trials like PRIMA and NOVA are consistent and primarily involve bone marrow suppression and gastrointestinal effects.[6]

• Hematologic: The triad of thrombocytopenia (low platelet count), anemia (low red blood cell count), and neutropenia (low neutrophil count) are the hallmark toxicities. In the NOVA trial, Grade 3 or 4 thrombocytopenia, anemia, and neutropenia were reported in 34%, 25%, and 20% of patients, respectively.[10] These rates were similar in the PRIMA trial's fixed-dose cohort, but were notably lower in the cohort that received the individualized starting dose, validating the dose-adjustment strategy.[9]
• Gastrointestinal: Nausea is very common, affecting a majority of patients, though it is typically Grade 1 or 2. Other common GI effects include constipation, vomiting, abdominal pain, and diarrhea.[2]
• Constitutional: Fatigue and asthenia (weakness) are very common and can impact quality of life.[2]
• Cardiovascular: Hypertension (high blood pressure) and palpitations are frequently observed.[6]
• Other Common Reactions: Musculoskeletal pain, decreased appetite, insomnia, headache, and dyspnea (shortness of breath) are also reported in a significant number of patients.[6]

Serious Warnings and Precautions

The FDA label for Zejula includes several critical warnings and precautions that clinicians must be aware of to ensure patient safety. These are not black box warnings, but they highlight potentially life-threatening risks.

• Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): This is the most serious long-term risk associated with Niraparib. Cases of these secondary hematologic malignancies, some of which have been fatal, have been reported in clinical trials and post-marketing surveillance.[5] The risk is low (approximately 0.8% to 3.8% in trial populations) but significant.[6] It appears to be a class effect for DNA-damaging agents, as all patients who developed MDS/AML had received prior chemotherapy with platinum agents or other DNA-damaging drugs.[15] This suggests a cumulative risk from sequential assaults on the genome of hematopoietic stem cells. The label mandates that any patient with suspected MDS/AML or prolonged hematologic toxicity be referred to a hematologist for evaluation, including bone marrow analysis. If MDS/AML is confirmed, Niraparib must be permanently discontinued.[6]
• Bone Marrow Suppression: This is the most common and immediate serious toxicity. It is a direct, on-target effect of PARP inhibition on rapidly dividing hematopoietic cells in the bone marrow.[24] To manage this risk, the label requires a strict monitoring schedule: complete blood counts (CBCs) must be tested weekly for the first month of treatment, monthly for the next 11 months, and periodically thereafter.[6] Treatment should not be initiated until patients have recovered from hematologic toxicity caused by prior chemotherapy (to Grade ≤1). Detailed dose modification guidelines for interruption and reduction are provided to manage clinically significant decreases in blood counts.[6]
• Cardiovascular Effects: Niraparib can cause or exacerbate hypertension, and cases of hypertensive crisis have been reported.[15] This may be related to off-target inhibition of dopamine, norepinephrine, and serotonin transporters.[27] Blood pressure and heart rate must be monitored at least weekly for the first two months, then monthly for the first year, and periodically thereafter. Patients with pre-existing cardiovascular disorders should be monitored closely, and hypertension should be managed with antihypertensive medications and, if necessary, dose adjustment of Niraparib.[6]
• Posterior Reversible Encephalopathy Syndrome (PRES): This is a rare but serious neurological syndrome that has been reported in patients treated with Niraparib. Symptoms include seizure, headache, altered mental status, and visual disturbances. A diagnosis requires confirmation by brain imaging. If PRES is suspected, Niraparib should be discontinued immediately and appropriate treatment administered.[15]
• Embryo-Fetal Toxicity: As a genotoxic agent that targets actively dividing cells, Niraparib can cause harm to a developing fetus. It is contraindicated in pregnancy. Females of reproductive potential must be advised of the risk and must use effective contraception during treatment and for 6 months after the final dose.[6]

Drug Interactions and Use in Specific Populations

Due to its metabolism by carboxylesterases rather than the CYP450 system, Niraparib has a low potential for pharmacokinetic drug-drug interactions, a significant clinical advantage.[2] However, pharmacodynamic interactions are possible, and caution is advised when co-administering Niraparib with other myelosuppressive drugs. The use of live vaccines is generally not recommended during treatment.[11]

Dose adjustments are recommended for patients with moderate hepatic impairment (200 mg starting dose), but no specific recommendations are available for patients with severe hepatic impairment or severe renal impairment (CrCl <30 mL/min), as they have not been studied.[11]

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Table 5: Common (≥10%) and Serious Adverse Reactions Associated with Niraparib

Adverse Reaction	Frequency (All Grades %)	Frequency (Grade 3-4 %)	Management/Monitoring Recommendation	Source Snippet(s)
Thrombocytopenia	50 - 61%	28 - 39%	Monitor CBCs weekly for 1st month, then monthly. Withhold/reduce dose per label.	2
Anemia	50%	25 - 33%	Monitor CBCs weekly for 1st month, then monthly. Withhold/reduce dose per label. Consider transfusion.	2
Neutropenia	23 - 30%	13 - 21%	Monitor CBCs weekly for 1st month, then monthly. Withhold/reduce dose per label.	2
Nausea	57 - 73%	<5%	Antiemetic prophylaxis. Consider bedtime dosing.	2
Fatigue/Asthenia	57%	8%	Patient education and supportive care.	2
Hypertension	20%	6 - 9%	Monitor BP/heart rate weekly for 2 months, then monthly. Manage with antihypertensives and dose modification.	6
MDS/AML	<1%	<1%	Monitor for prolonged hematologic toxicity. Refer to hematologist if suspected. Discontinue if confirmed.	6
PRES	0.1%	0.1%	Monitor for neurological symptoms. Discontinue immediately if suspected. Confirm with brain imaging.	15

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Dosing, Administration, and Chemical Synthesis

The practical application of Niraparib in the clinic requires a clear understanding of its distinct dosing regimens, which have been refined over time to optimize the balance between efficacy and safety. Furthermore, an appreciation of the complexity of its chemical synthesis provides context for its development and cost.

Dosing Regimens and Administration

The recommended dosing for Niraparib varies depending on the specific clinical indication, a nuance that reflects the evidence gathered from different pivotal trials.

• First-Line Maintenance of Advanced Ovarian Cancer: For this indication, an Individualized Starting Dose (ISD) is mandatory. This strategy was developed to mitigate the high rates of hematologic toxicity seen with a fixed dose. The dose is determined by the patient's baseline body weight and platelet count.[6]
• 200 mg (two 100-mg capsules) taken orally once daily for patients weighing less than 77 kg (170 lbs) OR who have a baseline platelet count of less than 150,000/µL.
• 300 mg (three 100-mg capsules) taken orally once daily for patients weighing 77 kg or more AND who have a baseline platelet count of 150,000/µL or more.
• Maintenance Treatment of Recurrent Ovarian Cancer: For this indication, the recommended dose is a fixed 300 mg (three 100-mg capsules) taken orally once daily.[6] This reflects the dosing regimen used in the foundational NOVA trial for this patient population.

Administration Guidelines:

Patients should be instructed to take their dose of Niraparib at approximately the same time each day to maintain steady plasma concentrations.23 The capsules can be taken with or without food. To help manage the common side effect of nausea, bedtime administration may be a useful strategy.23 The capsules must be swallowed whole and should not be chewed, crushed, or split.30 Treatment should continue until disease progression or the development of unacceptable toxicity.

Dose Modifications for Adverse Reactions

A cornerstone of Niraparib therapy is the proactive management of adverse reactions through dose modification. The prescribing information provides detailed protocols for interrupting treatment and subsequently reducing the dose in response to both hematologic and non-hematologic toxicities.[6] The standard dose reduction steps are from 300 mg to 200 mg, and then to a final step of 100 mg. If a dose below 100 mg per day is required to manage toxicity, Niraparib should be permanently discontinued.[24]

Overview of Chemical Synthesis

The large-scale manufacturing of Niraparib is a complex synthetic challenge, primarily due to the need to create the specific (S)-enantiomer of the piperidine ring with high purity. Early laboratory-scale syntheses were lengthy and inefficient, with one reported route involving 11 total steps and yielding only an 11% overall yield.[18] A significant bottleneck in this initial process was the use of chromatographic resolution to separate the desired chiral intermediate, a technique that is not practical or cost-effective for industrial production.[18]

To overcome these limitations, significant process development efforts were undertaken, leading to the invention of novel, more efficient, and scalable asymmetric synthetic routes.[18] A state-of-the-art approach employs a convergent strategy, where the two main heterocyclic fragments of the molecule are synthesized separately and then joined together in a late-stage coupling reaction.

Key Steps in an Advanced Convergent Synthesis:

1. Preparation of the Indazole Fragment: Synthesis of the 2H-indazole-7-carboxamide core structure.
2. Asymmetric Synthesis of the Piperidine Fragment: This is the most critical and innovative part of the process. Instead of relying on inefficient resolution, advanced methods like transaminase-mediated dynamic kinetic resolution are used. In this biocatalytic approach, an enzyme (a transaminase) is used to selectively convert a racemic starting material (an aldehyde surrogate) into the desired (S)-enantiomer of the piperidine precursor with very high enantiomeric excess.[18] This use of enzymes represents a significant advance in green and efficient pharmaceutical chemistry.
3. Fragment Coupling: The two fragments are joined together using a high-yielding and regioselective copper-catalyzed N-arylation reaction. This step forms the crucial carbon-nitrogen bond between the phenyl ring and the indazole nitrogen.[18]
4. Final API Formulation: The coupled product undergoes final chemical transformations, including deprotection of any protecting groups used during the synthesis, followed by salt metathesis to form and crystallize the desired final API, niraparib tosylate monohydrate.[16]

This evolution from a low-yield, resolution-based synthesis to a high-yield, asymmetric, convergent synthesis was essential for the commercial viability of Niraparib. It highlights the critical role that chemical process innovation plays in bringing a novel drug from the laboratory to patients.

Synthesis and Expert Recommendations

Niraparib has firmly established itself as a potent, first-in-class PARP inhibitor that has altered the treatment landscape for advanced ovarian cancer. Its clinical story is one of profound efficacy in delaying disease progression, counterbalanced by a significant but manageable toxicity profile. The evolution of its regulatory approvals, shaped by maturing long-term data, provides a clear roadmap for its optimal use and serves as an important case study for the entire class of DNA repair inhibitors.

Synthesis of Niraparib's Clinical Profile

Strengths:

• Proven PFS Efficacy: Niraparib has demonstrated a consistent, statistically significant, and clinically meaningful improvement in Progression-Free Survival across multiple settings: first-line maintenance for HRD-positive patients, recurrent maintenance for all platinum-sensitive patients, and as a treatment in late-line HRD-positive disease.
• Convenient Oral Dosing: The once-daily oral administration offers a significant quality-of-life advantage over intravenous therapies.
• Favorable Pharmacokinetic Profile: Its metabolism via carboxylesterases, bypassing the cytochrome P450 system, gives it a very low potential for common pharmacokinetic drug-drug interactions, simplifying its use in patients on multiple medications.

Limitations:

• Significant Hematologic Toxicity: Bone marrow suppression is the primary dose-limiting toxicity. The high incidence of Grade 3/4 thrombocytopenia and anemia necessitates intensive monitoring and frequent dose modifications, adding complexity to its management.
• Lack of Demonstrated Overall Survival Benefit: In the pivotal PRIMA and NOVA trials, the substantial PFS benefit did not translate into a statistically significant improvement in Overall Survival. While likely confounded by the effective use of crossover therapies, this lack of an OS benefit complicates risk-benefit discussions and has led to a more restricted first-line indication.
• Narrowing Therapeutic Window in HR-Proficient Disease: In patients with HR-proficient tumors, the magnitude of the PFS benefit is modest. When weighed against the risks of toxicity and the financial cost of treatment, its value proposition in this subgroup is less clear, a conclusion reflected in recent regulatory decisions.

Recommendations for Clinical Practice

Based on the totality of the evidence, the following recommendations are provided for the optimal integration of Niraparib into clinical practice:

1. Prioritize Biomarker-Guided Patient Selection: The use of Niraparib must be guided by biomarker status. In the first-line maintenance setting, its use should be restricted to patients with HRD-positive tumors (either a deleterious BRCA mutation or high genomic instability), as this is the population with the clearest and most durable benefit. For recurrent, platinum-sensitive maintenance, Niraparib remains a strong option for all patients, but the magnitude of benefit is greatest in those with HRD. All patients with newly diagnosed ovarian cancer should undergo comprehensive germline and somatic tumor testing to inform these decisions.
2. Mandate Proactive and Individualized Toxicity Management: Clinicians must not use a "one-size-fits-all" approach. The Individualized Starting Dose (ISD) regimen based on baseline weight and platelet count is mandatory for all patients starting first-line maintenance therapy. Vigilant monitoring of complete blood counts (weekly for the first month, then monthly) and blood pressure is non-negotiable. Clinicians and nursing staff must be prepared to implement dose interruptions and reductions promptly as per label guidelines to mitigate severe toxicity.
3. Conduct Comprehensive and Transparent Patient Counseling: Informed consent discussions must be nuanced. Patients should be clearly informed that Niraparib has a very high likelihood of delaying the progression of their cancer (PFS), which can provide a valuable chemotherapy-free interval. However, they must also understand that, based on current long-term data, it has not been shown to extend overall lifespan (OS). The potential reasons for this, such as the impact of subsequent therapies, should be explained. The small but serious long-term risk of developing MDS/AML must also be a part of this conversation.

Future Perspectives

The journey of Niraparib is far from over. Its future role will likely be defined by three key areas of investigation:

• Rational Combination Therapies: The future of PARP inhibition lies in combination strategies designed to enhance efficacy or overcome resistance. Ongoing clinical trials are exploring Niraparib in combination with immunotherapy (e.g., PD-1 inhibitors like dostarlimab), anti-angiogenic agents (e.g., bevacizumab), and other novel targeted agents (e.g., WEE1 inhibitors like azenosertib).[57] These combinations aim to attack cancer cells through multiple, synergistic mechanisms.
• Expansion into Other Tumor Types: The principle of synthetic lethality is not unique to ovarian cancer. Trials are actively investigating Niraparib's efficacy in other tumors known to harbor DNA repair defects, including BRCA-mutated breast cancer, prostate cancer, and pancreatic cancer.[27] The successful approval of a Niraparib-abiraterone combination for BRCA-mutated prostate cancer is a clear validation of this expansion strategy.[27]
• Overcoming Resistance: As with all targeted therapies, acquired resistance is a major challenge. Future research will focus on understanding the mechanisms by which tumors become resistant to Niraparib and developing strategies to re-sensitize them or bypass these resistance pathways, potentially with next-generation PARP inhibitors or novel drug combinations.

In conclusion, Niraparib is a powerful and important therapeutic agent that has provided a significant benefit to many women with advanced ovarian cancer. Its clinical story underscores the importance of personalized medicine, proactive toxicity management, and the need for long-term data to fully understand the value of novel cancer therapies.

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