PARP Inhibitors for

Ovarian CancerALLISON GUYTON, PHARMD, BCOP, BCPS

UNIVERSITY OF ALABAMA AT BIRMINGHAM, DEPARTMENT OF PHARMACY

Disclosure

I have nothing to disclose concerning possible

financial or personal relationships with

commercial entities (or their competitors) that

may be referenced in this presentation.

Objectives

Review the treatment guidelines for ovarian cancer

Discuss the role of PARP inhibitors in ovarian cancer

Understand basic pharmacology of FDA-approved

PARP inhibitors

Review pertinent literature evaluating PARP inhibitors in

ovarian cancer

Treatment Guidelines

Primary Treatment

Ovarian cancer, version 2.2017. J Natl Compr Canc Netw.

Primary Chemotherapy

Ovarian cancer, version 2.2017. J Natl Compr Canc Netw.

Persistent or Recurrent Disease

Ovarian cancer, version 2.2017. J Natl Compr Canc Netw.

PARP Inhibitors: Place in Therapy

Maintenance Therapy : Category 2A

Niraparib

Partial or complete response

Platinum –sensitive disease

Recurrent Disease: Category 2A

Preferred

Olaparib

Rucaparib

For platinum-resistant disease

Potentially active

Rucaparib

For platinum-sensitive disease

Ovarian cancer, version 2.2017. J Natl Compr Canc Netw.

Pharmacology

What is PARP?

PARP: Poly(ADP-ribose) polymerases

Family of 18 proteins

PARP1 and PARP2

Enzymes activated by DNA damage

Facilitate DNA repair in pathways involving single-strand

breaks (SSBs) and base excision repair (BER)

Annunziata, et al. Clin Cancer Res. 2010; 16(18):4517-26.

Dziadkowiec, et al. Menopause Rev 2016; 15(4): 215-19.

PARP Protein

.

Dziadkowiec, et al. Menopause Rev 2016; 15(4): 215-19.

PARP Inhibitors: Mechanism

Inhibition of PARP

Prevents repair of persistent SSBs

Leads to degradation into double strand breaks (DSBs)

BRCA mutated cells

Leads to homologous recombination (HR) deficiency

Rationale for PARP inhibitors

Prevent repair that occurs after cytotoxic chemotherapy

Synthetic lethality in cells with underlying HR defects

PARP inhibition with BRCA mutation results in genomic instability and cell death

Annunziata, et al. Clin Cancer Res. 2010; 16(18):4517-26.

Dziadkowiec, et al. Menopause Rev 2016; 15(4): 215-19.

PARP Inhibtors: Mechanism of Action

Olaparib (LynparzaTM) Rucaparib (Rubraca®) Niraparib (ZejulaTM)

Indication

Ovarian cancer, advanced:

Monotherapy of deleterious

germline BRCA-mutated advanced ovarian cancer in

patients who have been

treated with 3 or more prior

lines of chemotherapy

Ovarian cancer, advanced:

Monotherapy of deleterious

germline and/or somatic BRCA

mutation associated advanced ovarian cancer in

patients who have been

treated with 2 or more prior

lines of chemotherapy

Ovarian, fallopian tube, or

primary peritoneal cancer:

Maintenance treatment of recurrent epithelial ovarian,

fallopian tube, or primary

peritoneal cancer in patients

who are in a complete or

partial response to platinum-based chemotherapy

Olaparib(LynparzaTM)[package insert].Wilmington, DE. Astra Zeneca Pharmaceuticals LP;2017.Rucaparib(Rubraca®)[package insert].Boulder, CO. Clovis Oncology, Inc.;2017.Niraparib(ZejulaTM)[package insert].Waltham, MA. Tesaro, Inc.;2017.

PARP Inhibitors: Pharmacology

Olaparib (LynparzaTM) Rucaparib (Rubraca®) Niraparib (ZejulaTM)

Dose 400 mg (8 capsules) BID 600 mg (2 tablets) BID 300 mg (3 capsules) daily

AdjustmentsRenal ImpairmentCYP3A Inhibitors

Hepatic Impairment None

MonitoringCMP/CBC with differential

baseline and monthly CMP/CBC with differential

baseline and monthly

CMP/CBC with differential weekly for the first month, then

monthly

Monitor blood pressure and heart rate monthly during the

first year and periodically thereafter.

Olaparib(LynparzaTM)[package insert].Wilmington, DE. Astra Zeneca Pharmaceuticals LP;2017.Rucaparib(Rubraca®)[package insert].Boulder, CO. Clovis Oncology, Inc.;2017.Niraparib(ZejulaTM)[package insert].Waltham, MA. Tesaro, Inc.;2017.

Lab Abnormalities

Olaparib (LynparzaTM) Rucaparib (Rubraca®) Niraparib (ZejulaTM)

≥ 25%

Increase SCr

Increase MCV

Decrease Hgb

Decrease lymphocytes

Decrease in ANC

Decrease PLT

≥ 35%

Increase SCr

Increase ALT/AST

Decrease Hgb

Decrease lymphocytes

Increase cholesterol

Decrease PLT

Decrease in ANC

≥ 10%

Decrease PLT

Decrease Hgb

Decrease ANC

Decrease lymphocytes

Increase ALT/AST

Olaparib(LynparzaTM)[package insert].Wilmington, DE. Astra Zeneca Pharmaceuticals LP;2017.Rucaparib(Rubraca®)[package insert].Boulder, CO. Clovis Oncology, Inc.;2017.Niraparib(ZejulaTM)[package insert].Waltham, MA. Tesaro, Inc.;2017.

Side EffectsOlaparib (LynparzaTM) Rucaparib (Rubraca®) Niraparib (ZejulaTM)

≥ 20%

FatigueHeadache

Nausea/vomiting/diarrheaAnorexia Abdominal painDysgeusia

Nasopharyngitis/pharyngitis/URICough

Arthralgia/musculoskeletal painMyalgiaBack pain

Dermatitis/rash

≥ 20%

Fatigue

Nausea/vomitingConstipation > diarrhea

Abdominal painDysgeusia

Anorexia

Dyspnea

≥ 20%

FatigueHeadache

Insomnia

Nausea/vomitingDiarrhea/constipation

AnorexiaAbdominal pain/distention

Mucositis/stomatitis

NasopharyngitisDyspnea

Rash

Hypertension

Olaparib(LynparzaTM)[package insert].Wilmington, DE. Astra Zeneca Pharmaceuticals LP;2017.Rucaparib(Rubraca®)[package insert].Boulder, CO. Clovis Oncology, Inc.;2017.Niraparib(ZejulaTM)[package insert].Waltham, MA. Tesaro, Inc.;2017.

Clinical Evidence

Olaparib Clinical Studies

S.M. Domchek et al.

Single-arm

Patient population: germline BRCA-mutated advanced cancersy

Previously received 3 lines of chemotherap

Intervention: Olaparib 400 mg twice daily monotherapy

N= 137

ORR (95% CI) 34% (26 – 42)

CR 2%

PR 32%

Median DOR (95% CI) 7.9 months (5.6 – 9.6)

Rucaparib Clinical Studies

ARIEL 2

Multi-center, single-arm, open-label

Patient population: advanced BRCA-mutant ovarian cancer

Progression after 2 or more prior lines of chemotherapy

Intervention: Rucaparib 600 mg twice daily

N= 106

ORR (95% CI) 54% (44 – 64)

CR 9%

PR 45%

Median DOR (95% CI) 9.2 months (6.4 – 12.9)

Niraparib trial

NOVA

Double-blind, placebo-controlled

Patient population: recurrent epithelial ovarian, fallopian tube, or

primary peritoneal cancer following CR or PR to platinum-based therapy

Intervention: Niraparib 300 mg daily vs placebo

PFS HR (95% CI) P-value

gBRCAmut (n= 203) 74% 0.26 (0.17 – 0.41) < 0.0001

non- gBRCAmut

(n= 350)

55% 0.45 (0.34 – 0.61) < 0.0001

PARP Inhibitors for

Ovarian CancerALLISON GUYTON, PHARMD, BCOP, BCPS

AGUYTON@UABMC.EDU