parp inhibitors in ovarian cancer: a trailblazing and ... · ursula a. matulonis, m.d. dana-farber...

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PARP inhibitors in ovarian cancer: a trailblazing and transformative journey

Panagiotis A. Konstantinopoulos, MD, PhD and Ursula A. Matulonis, MD

Division of Gynecologic Oncology

Department of Medical Oncology

Dana-Farber Cancer Institute

Boston MA

Running title: PARP inhibitor development in ovarian cancer

Correspondence:

Ursula A. Matulonis, M.D.

Dana-Farber Cancer Institute

450 Brookline Ave

Boston, MA 02215

email: [email protected]

Phone: 617 632 2334

Fax: 617 632 3479

Dr. Matulonis reports conflicts of interest for 2X Oncology, Geneos, Fujifilm,

Immunogen, Merck (consulting) and Myriad Genetics (advisory board). Dr.

Konstantinopoulos reports conflicts of interest for Merck, Astrazeneca, Pfizer (advisory

boards).

Research. on June 11, 2020. © 2018 American Association for Cancerclincancerres.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 5, 2018; DOI: 10.1158/1078-0432.CCR-18-1314

mailto:[email protected]

http://clincancerres.aacrjournals.org/

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Grant support: Dr. Matulonis receives grant funding from the Breast Cancer Research

Foundation.

Abstract:

PARP inhibitors have transformed treatment for ovarian cancer, a cancer notable for

homologous recombination (HR) deficiencies and aberrant DNA repair, especially high

grade serous subtype. PARP inhibitors are now approved for recurrent ovarian cancer as

maintenance following response to platinum chemotherapy and BRCA mutated (BRCAm)

cancer treatment.




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In this issue of CCR, Ison et al (1) describes the United States Food and Drug

Administration (U.S. FDA) approval of the poly (ADP ribose) polymerase (PARP)

inhibitor niraparib which is the first PARP inhibitor to be approved by the U.S. FDA as

maintenance for recurrent ovarian cancer following response to platinum based

chemotherapy. This approval is part of a remarkable and transformative continuum of

establishment of the anti-cancer activity of PARP inhibitors by targeting DNA repair

deficiencies. The initial observation that PARP inhibitors have profound in vitro activity

against BRCA- mutated cancer cells was made in 2005 (2), activity of these agents in

patients with heavily pretreated BRCA-related cancers was shown in 2009 (3), the first

FDA approval of olaparib in 2014 for the treatment of germline BRCA mutated

(gBRCAm) ovarian cancer patients who have received at least 3 lines of prior

chemotherapy, and this current milestone of the first PARP inhibitor approved as

maintenance in patients with recurrent ovarian cancer following response to platinum

based chemotherapy (1). Ovarian cancer has been the model cancer to test these drugs

because of the enrichment, especially in high grade serous carcinoma (HGSC), of

underlying DNA repair deficiency which PARP inhibitors exploit through the mechanism

of synthetic lethality (4).

Niraparib is a potent inhibitor of PARP1 and PARP2. PARP1, the main member of the

PARP family, is a nuclear enzyme that transfers poly-ADP-ribosyl moieties from

nicotinamide-adenine-dinucleotide (NAD) to many target proteins in a post-translational

modification termed parylation. PARP1 contributes 85-90% of PARP activity (and




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NAD+ utilization) while 5-10% is facilitated by PARP2. PARP2 is PARP1’s closest

relative and exhibits almost overlapping functions as PARP1 (5); both enzymes are

involved in base excision repair. Additionally, PARP2 is essential for the viability of

PARP1 knockout mice as PARP1/PARP2 double knockout mice are not viable.

Parylation plays an important role in promoting DNA repair by allowing for recruitment

of proteins involved in repair of single-(SSB) and double-strand breaks (DSB) as well in

stalled-replication fork protection and restart (Figure 1). Inhibition of SSB and trapping

of PARP-DNA complexes at the replication fork are the most prevalent mechanisms of

action of PARP inhibitors against HR deficient cells although other mechanisms such as

replication fork collapse and enhancement of toxic classic non-homologous end joining

(C-NHEJ) have also been proposed. Beyond DNA repair, PARP1 has numerous

alternative functions (Figure 1) including regulation of transcription, angiogenesis,

adaptation to hypoxia, epithelial-mesenchymal transformation (EMT), metastasis,

inflammation and immune regulation. In this regard, the anticancer activity of PARP

inhibitors extends beyond DNA repair, and PARP inhibitors have been considered for

management of a number of non-oncological conditions (Figure 1) (6-9).

Niraparib has a maximally tolerated dose of 300 mg once daily, and following repeated

doses of niraparib, its mean half-life is 36.5 hours. Niraparib’s metabolism by

carboxylesterases to an inactive metabolite which then undergoes glucuronidation differs

from the other FDA-approved PARP inhibitors, olaparib and rucaparib, which instead are

metabolized through CYP enzymes. Niraparib has an off target effect of norepinephrine,

epinephrine and dopamine transporter interactions which likely gives rise to the toxicities




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of hypertension, headaches and palpitations.

In the NOVA study which led to the FDA maintenance approval, 553 patients with

recurrent platinum sensitive HGSC, sensitive to their penultimate platinum as well as

most recent platinum regimen were randomized 2:1 to either niraparib or placebo at the

completion of chemotherapy and were prospectively placed into one of 2 groups,

gBRCAm or non-gBRCAm mutated based on upfront germline BRCA testing. Within the

non-gBRCAm group, patients were further stratified by retrospectively performed HR

deficiency (HRD) testing (10). Efficacy results were performed simultaneously for the

gBRCA and non-gBRCA groups, and the primary endpoint was progression-free survival

measured from the time of treatment randomization to cancer progression or death from

any cause. Independent radiologic review was used to define cancer progression.

Niraparib significantly improved median progression free survival (PFS) in all the 3

primary efficacy groups – which included gBRCAm, overall non-gBRCAm and non-

gBRCA/HRD positive, as well as in the exploratory groups including somatic

BRCAm/HRD positive, BRCA wild-type/HRD positive and even in the HRD

negative/BRCA wild-type group. Because of the observed myelosuppression of niraparib

and especially the 33% risk of grade 3 and 4 thrombocytopenia observed in the NOVA

study, the FDA package insert contains detailed recommendations for weekly blood

count assessment for the first month after starting niraparib, then monthly thereafter, as

well as specific dose modifications for myelosuppression management.

This FDA approval of niraparib has been transformative for many reasons; though the




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NOVA study eligibility excluded any cancers but HGSC, the FDA approval was

histology non-specific, thus allowing any ovarian cancer patient irrespective of their

cancer’s histology to receive niraparib as long as there is demonstration of benefit from

platinum. Platinum and PARP inhibitors have overlapping mechanisms of response and

resistance, thus the use of a PARP inhibitor in the maintenance setting serves to improve

remission length post response to platinum. Additionally, the approval was based on PFS

improvement, and for several reasons, survival benefit may not be observed in

maintenance studies because of the availability of PARP inhibitors and eventual

crossover of placebo patients to PARP inhibitor use (11).

Two other phase III PARP inhibitor maintenance studies have been published, SOLO2

and ARIEL3, both of which have also led to FDA approvals of olaparib and rucaparib,

respectively, as maintenance therapies, and clinicians in the United States now have 3

PARP inhibitors to select from in the maintenance setting (12, 13). The PFS benefits in

the BRCAm and the HRD positive groups in these phase 3 studies are remarkably similar

leading to the conclusion that these drugs have comparable efficacy. Besides PARP

inhibitor toxicities that include gastrointestinal, bone marrow suppression, and some

fatigue, an initial safety signal of early PARP inhibitor studies was an increased risk of

MDS and AML, but in these phase 3 maintenance studies, the MDS and AML risk seems

quite comparable for the PARP inhibitor and placebo-treated patients.

Additionally, PARP inhibitor combinatorial strategies are actively being explored.

Several rationales exist behind these combinations including overcoming PARP inhibitor




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resistance by addition of agents that inhibit HR in tumors with de novo or acquired HR

proficiency or priming the immune system by PARP inhibitors to facilitate response to

immune checkpoint blockade in both HR deficient and proficient tumors. Combinations

that have reached phase 3 testing include olaparib and the anti-vascular agent cediranib;

noteworthy phase 2 results (14) of efficacy in BRCAwt as well as BRCAm ovarian cancer

have led to randomized studies in both BRCAm and BRCAwt recurrent cancer

(NCT02446600 and NCT02502266). Additionally, phase 2 studies of combined PARP

inhibitor and immune checkpoint blockade, including niraparib and pembrolizumab

(NCT02657889), in platinum resistant ovarian cancer have also yielded notable early

results, especially so because of the relatively low overall response rate of single agent

checkpoint blockade for recurrent ovarian cancer.

Lastly, PARP inhibitors have activity beyond ovarian cancer; olaparib has shown

impressive activity in both BRCAm breast cancer and prostate cancer. With the increased

use of next generation sequencing and identification of mutated genes involved in DNA

repair, PARP inhibitors are poised for use as single agents in cancers with documented

abnormalities in DNA repair. Additionally, because of PARP enzymes’ multiple

functions in cancer cells, combination strategies with non-myelosuppressive biologic

agents may offer patients with DNA repair proficient cancers an opportunity to benefit

from a PARP inhibitor.




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Figure 1 Legend:

PARP1 functions, results of PARP inhibition and clinical/translational applications

of PARP inhibitors.

Top panel: PARP1 functions in repair of DNA damage. PARP1 participates in SSB and

DSB repair as well in stalled-replication fork protection and restart. Inhibition of SSB and

trapping of PARP-DNA complexes at the replication fork are the most prevalent

mechanisms of action of PARPis against HR deficient cells although other mechanisms

such as replication fork collapse, enhancement of toxic classic non-homologous end

joining (C-NHEJ) and induction of alternative end joining (Alt-EJ) in PARP1-deficient

cells have also been proposed. Besides anticancer activity, unresolved DSBs may induce

immune “priming” of the tumor for response to PD-1/PD-L1 inhibitors via activation of

innate immunity (via activation of STING pathway) and by upregulation of PD-L1

expression in cancer cells.

Bottom panel: PARP1 functions beyond DNA damage repair. 1) PARP1 serves as a

potent modulator of gene transcription, through activities that include transcription factor

(TF) regulation, chromatin regulation, and the ability of PARP1 to serve as

transcriptional co-regulator and chromatin modifier. PARP1 also interacts with RNA

polymerase (pol) II complexes, and can thus both up- or down-regulate gene expression.

PARP inhibition leads to context-specific stimulation or inhibition of gene expression

which can be exploited in both oncologic and benign indications. 2) PARP1 promotes

angiogenesis via upregulation of transcription of proangiogenic factors such as syndecan-

4 and Id-1 as well as activation of HIF1α. PARP1 inhibition impairs angiogenesis and

this can also explain part of the anti-cancer activity of PARP inhibitors as well as provide




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the rationale for combinations with anti-angiogenic agents. 3) PARP1 also induces

epithelial-mesenchymal transition (EMT) by upregulating vimentin and Snail1 as well as

can induce metastasis by activation of ETS and NF-kB transcription factors; PARP

inhibition can therefore inhibit EMT and metastasis. 4) Activation of PARP1 occurs by

reactive oxygen species (ROS) and contributes to stimulation of inflammation via

upregulation of NF-kB, NFAT and AP-1 transcription factors. 5) Furthermore, PARP1

has been closely implicated with modulation of the immune response; beyond activation

of NF-kB (in macrophages and dendritic cells) and of NF-AT (T cells), PARP1 increases

the expression of pro-inflammatory cytokines, of interleukin-2 (IL-2) and T helper type 2

(Th2) cytokines while it decreases Foxp3+ regulatory T cells (Tregs). Due to these

inflammatory and immunologic properties, PARP inhibitors have been proposed for the

management of several acute and chronic inflammatory conditions, as well as to limit

tissue damage during reperfusion in acute events, such as myocardial infarction (MI),

circulatory shock or brain stroke.

H1: histone H1, NF-kB: nuclear factor kappa-light-chain-enhancer of activated B cells,

HIF1a: hypoxia-inducible factor 1-alpha, ETS: E26 transformation-specific, NFAT:

Nuclear factor of activated T-cells, AP-1: activator protein-1, IL-2: interleukin-2, Th2:

Type 2 helper T cells, Foxp3: forkhead box P3, Tregs: regulatory T cells, MI: myocardial

infarction.




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References:

1) Ison G, Howie LJ, Amiri-Kordestani L, Zhang L, Tang S, Sridhara R et al. FDA

Approval Summary: Niraparib for the maintenance treatment of patients with recurrent

ovarian cancer in response to platinum-based chemotherapy. Clin Cancer Research 2018

2) Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB et al.

Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature

2005; 434:917-21.

3) Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M et al. Inhibition of

Poly(ADP-Ribose) polymerase in tumors from BRCA mutation carriers. NEJM 2009;

361:123-134.

4) Konstantinopoulos P, Ceccaldi R, Shapiro GI, D’Andrea AD. Homologous

recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer.

Cancer Discovery 2015;5:1137-54.

5) Ménissier de Murcia J, Ricoul M, Tartier L, Niedergang C, Huber A, Dantzer F et al.

Functional interaction between PARP-1 and PARP-2 in chromosome stability and

embryonic development in mouse. EMBO J. 2003;22:2255-63.

6) Rosado MM, Bennici E, Novelli F, and Pioli C. Beyond DNA repair, the

immunological role of PARP-1 and its siblings. Immunology 2013;139:428-437.




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7) Tentori L, Lacal PM, Muzi A, Dorio AS, Leonetti C, Scarsella M et al. Poly(ADP-

ribose)polymerase inhibition or PARP-1 gene deletion reduces angiogenesis. European J of

Cancer 2007;43:2124-2133.

8) Knudsen K, de Bono JS, Rubin MA, Feng FY. Chromatin to Clinic: The molecular

rationale for PARP1 inhibitor function. Mol Cell 2015;58:925-934.

9) Bai P. Biology of Poly(ADP-ribose)polymerases: The Factotums of Cell Maintenance.

Cell 2015;58:947-958.

10) Mirza MR, Monk BJ, Herrstedt J, Oza AM, Mahner S, Redondo A, et al. Niraparib

Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. New Engl J of

Medicine 2016;375:2154-2164.

11) Matulonis UA, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al.

Olaparib maintenance therapy in patients with platinum-sensitive, relapsed serous ovarian

cancer and a BRCA mutation: Overall survival adjusted for postprogression

poly(adenosine diphosphate ribose) polymerase inhibitor therapy. Cancer

2016;122:1844-52.

12) Pujade-Lauraine E, Ledermann JA, Selle F, Gebski V, Penson RT, Oza AM et al.

Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed

ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind,




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randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18:1274-1284.

13) Coleman RL, Oza AM, Lorusso D, Aghajanian C, Oaknin A, Dean A et al. Rucaparib

maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy

(ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet.

2017;390:1949-1961.

14) Liu JF, Barry WT, Birrer M, Lee JM, Buckanovich RJ, Fleming GF et al. A

randomized phase 2 study of combination cediranib and olaparib versus olaparib alone as

recurrence therapy in platinum-sensitive ovarian cancer. Lancet Oncol 2014;15:1207-14.




Figure 1:

© 2018 American Association for Cancer Research

PARP1

PARP1

PARP1

Single-strand breakrepair

Collapse of replicationforks

Error-prone DNA repairGenomic instability

Anticancer and anti-inflammatory activities

Anticancer activity andrationale for combinationswith antiangiogenic agents

Anticancer activity

Anticancer activity

Potential in treatment ofchronic inflammatory

conditions such as multiplesclerosis, allergy/asthma,

rheumatoid arthritis

Potential in treatment ofacute events such as stroke,

MI, shock

Inhibition of angiogenesis

Anti-inflammatory activity

Immune tolerance

Inhibition of metastasisand cancer cell invasion

↓ Tissue damage duringreperfusion injury

↓ Inflammation →↓ tumor growth

Context-specificstimulation or inhibition of

gene expression andtranscription factor

programs

Trapping of PARP onDNA damage

Formation of DSBs

• Unresolved DSBs activateinnate immunity (STINGpathway) and upregulatePD-L1 leading to immune“priming” for responseto PD-1/PD-L1 inhibitors

• Anticancer activity due tosynthetic lethality againstHRD tumors

Replication fork protectionand restart

Inhibition of C-NHEJInduction of Alt-EJ

Histone H1Transcription

regulation

Angiogenesis andadaptation tohypoxia

EMT/metastasis

Immuneregulation

Inflammatorystimulation

↑ ERK activation

↑ HIF1α

↑ Proangiogenic factors (syndecan, Id-1)

↑ Vimentin, Snail1

↑ NF-κB, ETS

↑ IL-1, TNFα production

↑ NF-κB, NFAT, AP-1

↑ Proinflammatory cytokines

↑ IL-2, Th2 cytokines

↓ Foxp3+ Tregs

↑ PARP1 is activated by ROS

↑ NF-κB, NFAT, AP-1

Such as NF-κB, Elk1

TFRNApol II

Chromatin modulation

Stalledfork

PARP1 functions

DN

A d

amag

e re

pair

Bey

ond

DN

A d

amag

e re

pair

Result of PARP-inhibition Possible clinical andtranslational applications




Published OnlineFirst June 5, 2018.Clin Cancer Res Panagiotis A. Konstantinopoulos and Ursula A Matulonis transformative journeyPARP inhibitors in ovarian cancer: a trailblazing and

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