SUMMARY

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    • Video: Mechanism of Action
• Niraparib is an orally available, highly selective poly adenosine diphosphate (ADP)-ribose polymerase inhibitor (PARPi), with potent activity against PARP-1 and PARP-2 deoxyribonucleic acid (DNA) repair polymerases.¹
• Abiraterone acetate is a prodrug that is converted in vivo to abiraterone, an androgen biosynthesis inhibitor, that selectively inhibits the enzyme 17-α hydroxylase/C17,20-lyase (CYP17). Inhibition of CYP17, which is expressed in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis, may result in²:
  • Increased adrenal production of mineralocorticoids (aldosterone).³
  • Interruption of the negative feedback control of adrenocorticotropic hormone (ACTH).^3,4
    • The resulting high levels of ACTH and steroid precursors upstream of CYP17 may lead to increased mineralocorticoid effects such as hypertension, hypokalemia, and fluid retention.
    • Coadministration of a corticosteroid suppresses ACTH, resulting in a reduction of steroids upstream of the CYP17 blockade that may ameliorate mineralocorticoid effects.³
• The combination of niraparib and abiraterone acetate offers a dual-action approach to target tumors with BRCA1/2 mutations in metastatic castration-resistant prostate cancer (mCRPC).^5,6 Disruption of homologous recombination repair (HRR) mechanisms by abiraterone acetate potentially sensitizes prostate cancer cells to treatment with niraparib as the combination allows for the simultaneous inhibition of two distinct mechanisms of DNA repair: androgen receptor (AR)-regulated HRR and PARP-associated base-excision repair.^7,8

BACKGROUND

Role of PARP in DNA Repair and Defective Homologous Recombination Repair (HRR)

In healthy cells, damage to cellular DNA is repaired by a variety of mechanisms, including HRR and PARP-mediated base-excision repair.⁹ However, mutations and aberrations in genes involved in DNA repair processes can promote tumorigenesis and inappropriate cell proliferation.¹⁰ Highly prolific cancer cells are generally more prone to DNA single-strand breaks (SSBs) which evade cell death through an array of complex DNA repair pathways, including activation of PARPs.¹¹ PARPs are a 17-member superfamily of enzymes involved in the synthesis of poly ADP-ribose (PAR) using nicotinamide adenine dinucleotide (NAD+) as a substrate.¹² PAR, a signaling molecule that is synthesized in response to DNA-strand breaks, regulates maintenance of DNA integrity, gene expression, and cell division.¹³ PARP-1 and PARP-2 are specifically classified as DNA damage-dependent PARPs based on the ability to detect and promote the repair of DNA SSBs using base-excision repair, thereby allowing cancer cells to survive.^14,15

When PARPis trap PARP-1 and PARP-2 enzymes at the site of DNA damage, this can lead to the accumulation of double-strand breaks (DSBs) which are normally repaired by HRR, an error-free mechanism that makes use of the sister chromatid as a template.^14,16 Molecular defects in HRR result in faulty proteins and lead to the use of an alternative, error-prone mechanism known as non-homologous end-joining (NHEJ) repair that contributes to genomic instability and cancer.¹¹ Additionally, DNA repair and cell survival become dependent on base excision-repair via PARP enzymes,^16,17 thereby increasing susceptibility to pharmacological inhibition of DNA repair enzymes; a phenomenon known as synthetic lethality.^11,16

The PARPis, as a class of drugs, exploit synthetic lethality as a therapeutic strategy for the treatment of cancers with HRR deficiencies by competing with NAD+ for the binding to the catalytic domain of PARP. Inhibiting the catalytic activity of PARP-1 induces the accumulation of unrepaired SSBs that degenerate into more lethal DSBs during DNA replication.¹¹ PARPi-induced cytotoxic PARP-DNA complexes result in DNA damage, chromosomal instability, and death of HRR-deficient cells via apoptosis.¹⁴ Examples of HRR deficiencies include BRCA1/2 mutations and non-BRCA mutations such as ATM, BRIP1, CDK12, CHEK2, FANCA, HDAC2, and PALB2.¹¹

Rationale for Combining a PARPi with an AR-Signaling Inhibitor

AR signaling is one of the main pathways that drive prostate cancer growth.¹⁸ The AR regulates a network of DNA repair genes, one of which is the known AR-cofactor, PARP-1.⁹ In addition to facilitating DNA repair, PARP-1 may support AR transcriptional activity as a potent modulator of both AR function and response to DNA damage.¹⁹ PARP-1 also has protumorigenic effects in AR-positive prostate cancer by promoting AR occupancy and function.¹⁹ PARP inhibition, therefore has antitumor effects by disrupting AR-associated oncogenic signaling. In animal studies, HRR genes interact with AR signaling to regulate DNA repair in prostate cancer, suggesting that the combination of a PARPi and abiraterone acetate may be more effective in patients with HRR mutations.²⁰ Several studies in prostate cancer have also observed that treatment with PARPis in combination with abiraterone acetate improved radiographic progression-free survival (rPFS) compared to abiraterone acetate alone.¹¹ These results contribute to the hypothesis of a novel type of targeted therapy involving the interplay between PARPis and AR-signaling inhibitors.

CLINICAL PHARMACOLOGY

Niraparib - Description

Niraparib tosylate monohydrate, designated chemically as 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole 7-carboxamide 4-methylbenzenesulfonate hydrate, is a small-molecule selective inhibitor of the PARP-1 and PARP-2 enzymes with in vitro 50% inhibitory concentration (IC₅₀) = 3.8 and 2.1 nM, respectively.^1,12,21 Niraparib is a potent catalytic PARPi with selectivity for cancerous cells over normal cells.¹²

Abiraterone Acetate - Description

Abiraterone acetate, designated chemically as (3β)-17-(3-pyridinyl) androsta-5,16-dien-3-yl acetate, is the acetyl ester of abiraterone. Abiraterone acetate and its metabolite, abiraterone, are highly selective, potent, and irreversible inhibitors of CYP17 with a Ki_app of <1 nM and IC₅₀ of 72 nM.^22,23 In human microsomes, the IC₅₀ of abiraterone for inhibition of CYP17 was approximately 10% of the IC₅₀ of ketoconazole.²⁴

Mechanism of Action

The combination of niraparib and abiraterone acetate offers a dual-action approach to target tumors with BRCA1/2 mutations in mCRPC.^5,6 Niraparib is an orally available, highly selective PARPi with potent activity against PARP-1 and PARP-2.¹ Abiraterone acetate is a prodrug that is converted in vivo to abiraterone, an androgen biosynthesis inhibitor, that selectively inhibits the CYP17 enzyme, providing antitumor effects by inhibiting the production of androgens, such as testosterone, and the activation of the AR.^25,26 Inhibition of the AR reduces expression of DNA repair genes and NHEJ repair, which leads to accumulation of DNA damage, and results in a compensatory increase in PARP activity.^17,27,28 Disruption of HRR mechanisms by abiraterone acetate potentially sensitizes prostate cancer cells to treatment with niraparib as the combination allows for the simultaneous inhibition of two distinct mechanisms of DNA repair: AR-regulated HRR and PARP-associated base-excision repair.^7,8

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 20 May 2024.