PARP Inhibitors in Epithelial Ovarian Cancer

Kristin N. Taylor and Ramez N. Eskander*

Recent Patents on Anti-Cancer Drug Discovery
Rebecca and John Moores Cancer Center, Department of Reproductive Medicine, Division of Gynecologic Oncology, University of California, San Diego, La Jolla, CA, USA

A R T I C L E H I S T O R Y
Abstract: Background: Ovarian cancer remains the most common lethal gynecologic malignancy. The therapeutic gains with the use of traditional cytotoxic chemotherapy in advanced stage disease remain limited, reflecting the need for novel therapies. Poly(ADP-ribose) polymerase (PARP) inhibitors have recently demonstrated a significant therapeutic effect in patients with recurrent, high grade serous ovar- ian cancer, both in the treatment of existing disease and in prolonging the disease-free interval.
Objective: The purpose of this article is to discuss PARP inhibitor use in patients with advanced stage ovarian cancer, and to extensively review the existing clinical literature and related patents.

Methods: A comprehensive PUBMED literature review was conducted to identify all published phase

Received: July 04, 2017
Revised: November 28, 2017
Accepted: December 01, 2017

DOI: 10.2174/1574892813666171204094822
2 and phase 3 clinical trials involving PARP inhibitors in advanced epithelial ovarian cancer. Further, several patents related to PARP inhibitor use, companion diagnostic tests, and the development of bio- markers to predict PARP inhibitor responsiveness are described.
Results: PARP inhibitors have demonstrated significant clinical activity in both BRCA deficient and wild-type patient cohorts, with all three FDA-approved PARP inhibitors demonstrating efficacy irre- spective of BRCA mutation status in patients with advanced epithelial ovarian cancer.
Conclusion: PARP inhibitors have emerged as an exciting new drug class in the treatment of epithelial ovarian cancer. Ongoing studies are aimed at improving our ability to identify ideal candidates for PARP inhibitor therapy, as well as to identify and target mechanisms of drug resistance, and novel combinatorial approaches.

Keywords: BRCA mutation, homologous recombination deficiency, PARP inhibitor, poly (ADP-ribose) polymerase, ovarian cancer, synthetic lethality.

INTRODUCTION
It is anticipated that there will be 22,440 new cases of ovarian cancer in the United States in 2017, with 14,080 deaths [1]. Treatment for patients with advanced stage dis- ease includes maximal effort cytoreductive surgery followed by combination with platinum-based chemotherapy, to which most patients initially respond. However, approximately 70% of patients will ultimately develop disease recurrence and will require additional systemic chemotherapy [2]. Within this cohort of patients, subsequent therapeutic inter- ventions traditionally result in progressively shorter disease- free intervals, with the development of platinum resistance portending a poor prognosis. Given the limited therapeutic gains achieved with traditional cytotoxic agents, the explora- tion of novel therapeutic paradigms is warranted in an effort to improve oncologic outcome and patient-related quality of life.

*Address correspondence to this author at the 3855 Health Sciences Drive #0987, La Jolla, CA 92093 USA; Tel: 001-858-822-6199;
Fax: 001-858-822-6319; E-mail: [email protected]
BRCA
The identification of BRCA1 and BRCA2 germline muta- tions as conferring an increased risk for breast and ovarian cancer revolutionized the approach to both the prevention and treatment of these cancers [3-6]. Patients with a germline BRCA1/2 mutation constitute up to 18% of high grade serous Ovarian Cancer (OC) patients and are more likely to have platinum-sensitive disease, and a longer disease specific sur- vival [7]. As these are tumor suppressor genes, a second so- matic mutation of the wild-type copy of the BRCA1/2 gene, with a Loss of Heterozygosity (LOH), can lead to the devel- opment of cancer in germline mutation carriers [8].
The BRCA1 and BRCA2 proteins play an important role in the repair of DNA Double-Strand Breaks (DSBs) via the high-fidelity Homologous Recombination (HR) pathway. In the absence of HR pathway activity, DNA repair relies on error-prone nonhomologous end-joining (NHEJ) which is an alternative for repairing DSBs [9]. Cancer cells lacking func- tional BRCA1 or 2 proteins are considered deficient in ho- mologous recombination (HRD; Homologous Recombina- tion Deficiency) and display chromosomal instability [10].

2212-3970/18 $100.00+.00 © 2018 Bentham Science Publishers

PARP INHIBITION AND SYNTHETIC LETHALITY
Poly(ADP-ribose) polymerase (PARP) 1 and 2 are en- zymes that play an important role in the repair of Single Strand Breaks (SSBs) in DNA, primarily through the Base Excision Repair (BER) pathway [11]. PARP binds DNA at the location of the excised base, and when activated, recruits other DNA repair proteins [12]. Pharmacologic PARP inhi- bition blocks the catalytic activity of PARP, preventing re- pair of SSBs and leading to the development of DSBs at the replication fork, which are toxic to the cell, particularly those with HRD [10].
Another effect of PARP inhibition is PARP trapping, whereby PARP1 and PARP2 can be trapped on damaged DNA and unable to recruit DNA repair proteins, blocking DNA repair and ultimately leading to cell death [13]. Al- though all PARP inhibitors oppose the catalytic activity of PARP, there are striking differences in their abilities to trap PARP, which are related to the size and structure of the molecule and are correlated with the potency of the specific PARP inhibitor when used as a single agent. This further accounts for the significant differences in dosing among PARP inhibitors, with the most potent PARP trapping agent talazoparib being dosed at 1mg daily, as compared to 300mg or greater daily with all other PARP inhibitors [14]. PARP trapping is also the likely mechanism by which PARP inhibi- tors exert their cytotoxic effects in HR-proficient cells [15].
BRCA mutation or PARP inhibition occurring independ- ently in a cell is not detrimental, but when combined in one cell, becomes lethal. This phenomenon, known as synthetic lethality, is the ability to cause cell death, which is “synthe- sized”, or created, when the two such events are combined. Given this concept of synthetic lethality, PARP inhibition has been evaluated in BRCA1/2-deficient tumor cells, with up to a 1000-fold increased sensitivity relative to BRCA wild-type tumor cells [10, 16]. This effect was also seen in a mouse xenograft model using BRCA2-deficient tumors cells which, when treated with PARP inhibitor for five days, dis- played significant regression relative to BRCA wild-type tumors [17]. These impressive findings catalyzed the inves- tigation of PARP inhibitors in human clinical trials, begin- ning with olaparib.
OLAPARIB
Olaparib is the most extensively studied PARP inhibitor, with an initial patent filing in breast and pancreatic cancers (US20160051517) [18]. On December 19, 2014, olaparib was the first PARP inhibitor to be FDA-approved for use in patients with germline BRCA-mutated high grade serous ovarian, fallopian tube, or primary peritoneal carcinoma fol- lowing three or more prior lines of therapy (Table 1) [19-24]. A second indication for use has more recently been granted by the FDA on August 17, 2017, for maintenance following a complete or partial response to platinum-based chemother- apy, irrespective of BRCA mutation status.
EARLY EFFICACY DATA
Early Phase I and II trials of olaparib monotherapy dem- onstrated promising efficacy signals in cohorts with recurrent OC, with a response rate ranging from 31-41% in those with
a germline BRCA1/2 mutation [25-29], and 24% in patients with no identifiable BRCA mutation [28], at a dose of 400mg twice daily (BID). Subsequently, two larger Phase II trials demonstrated a benefit in Progression-Free Survival (PFS) in the maintenance setting, and a significant tumor response in the treatment setting, the latter of which led to the FDA ap- proval of olaparib as the first PARP inhibitor for the treat- ment of recurrent ovarian cancer in patients harboring a BRCA germline mutation (Table 1).
The first, Study 19, was a randomized, double-blind, pla- cebo-controlled, Phase II study of the use of olaparib as maintenance therapy in the setting of recurrent, platinum- sensitive OC [20]. Patients were eligible regardless of BRCA mutation status, and must have received two or more prior lines of chemotherapy, with a Partial (PR) or Complete Re- sponse (CR) to the last platinum-based chemotherapy. Two hundred sixty-five patients were enrolled and randomized to olaparib 400mg bid or placebo. Those who received olaparib had a significantly prolonged progression-free survival (PFS) (8.4 months vs. 4.8 months, hazard ratio (HR) 0.35, 95% confidence interval (CI) 0.25-0.49, p < 0.001). This PFS ad- vantage persisted in all subgroup analyses. In a planned analysis of BRCA germline mutation carriers, the benefit was magnified, with a nearly 8-month improvement in median PFS (11.2 months vs. 4.3 months, HR 0.18, 95% CI 0.10- 0.31, p < 0.0001). Despite the above data, the FDA Oncol- ogy Drug Advisory Committee (ODAC) rejected the applica- tion for a maintenance olaparib label in this setting. An analysis of Overall Survival (OS) at 77% maturity did not demonstrate a significant difference between the olaparib and placebo groups (median OS 29.8 months vs. 27.8 months, HR 0.73, 95% CI 0.55-0.96, p = 0.025, which did not meet threshold for significance of p = 0.0095) [30]. However, with the exclusion of those in the placebo group who received olaparib after progression of disease, there was a significant OS benefit in the olaparib group among BRCA mutation carriers (HR 0.52, 95% CI 0.28-0.97), suggesting a
confounding effect [30].
A subsequent single-arm trial, Study 42, evaluated ola- parib as treatment for patients with recurrent, platinum- resistant OC and a germline BRCA1/2 mutation [19]. One hundred ninety-three patients were administered olaparib 400mg bid until disease progression or toxicity. The Objec- tive Response Rate (ORR) was 31.1% (95% CI 24.6-38.1%), with stable disease of at least 8 weeks in 40% of patients. Median PFS and OS were 7 months and 16.6 months, re- spectively. In a subgroup analysis of 137 patients with three or more prior lines of chemotherapy, olaparib was found to be similarly effective, with an ORR of 34%. After consider- ing the data from this heavily pre-treated cohort, the FDA granted accelerated approval for olaparib, specifically for treatment as fourth-line chemotherapy in germline BRCA mu- tation carriers. A companion diagnostic blood test, BRACA- nalysis CDx (Myriad) (US6895337) [31], was approved in parallel to identify patients carrying BRCA gene mutations.
PREDICTORS OF RESPONSE TO OLAPARIB
Although olaparib is thought to be most effective in BRCA-mutated tumors, the role of olaparib in those with sporadic OC has been explored. An early Phase II study was

Drug Indications for Use Trial Design Patient Population Regimen Outcome Grade 3/4 AEs Ref.

Olaparib Treatment in recurrent OC, with 3+ prior regimens (germline BRCA1/2
mutation) Study 42 (NCT01078662) Phase II, single-arm -Recurrent, platinum- resistant OC
-Germline
BRCA1/2
-1+ prior regi- mens Olaparib 400mg bid as treatment ORR:
-31.1% (overall)
-34% (3+ prior regimens) Anemia, abdominal pain, fatigue [19]
Maintenance in recurrent, platinum- sensitive OC (any BRCA mutation status) Study 19 (NCT00753545) Phase II, randomized -Recurrent, platinum- sensitive OC
-Any BRCA
mutation status
-2+ prior regi- mens Olaparib 400mg bid vs. placebo as maintenance PFS (months):
-Olaparib = 8.4
-Placebo = 4.8 Nausea, fa- tigue, vomit- ing, anemia [20]
SOLO-2 (NCT01874353) Phase III, RCT -Recurrent, platinum- sensitive OC
-PR or CR to recent platinum chemotherapy
-Germline
BRCA1/2
-2+ prior regi- mens Olaparib 300mg bid vs. placebo as maintenance PFS (months):
-Olaparib 19.1
-Placebo 5.5 Anemia, neutropenia, fatigue, nau- sea, vomiting [21]

Ruca- parib Treatment in recurrent OC, with 2+ prior regimens (germline or somatic BRCA1/2
mutation) Study 10 (Part 2A)
(NCT01482715) Phase I (dose- escalation), Phase II (expansion, single-arm) -Recurrent, platinum- sensitive OC - Germline BRCA1/2
-2-4 prior regi- mens Rucaparib 600mg bid as treatment ORR: 59.5% Fatigue, ane- mia, elevated AST/ALT [22]
ARIEL2 (Part 1) (NCT01891344) Phase II, single-arm -Recurrent, platinum- sensitive OC - Any BRCA mu- tation status
-1+ prior regi-
mens Rucaparib 600mg bid as treatment PFS (months):
-Germline or so- matic BRCA1/2 = 12.8
-LOH high = 5.7
-LOH low = 5.2 Anemia, elevated AST/ALT [23]

Niraparib Maintenance in platinum- sensitive OC, 2+ prior regi- mens (any BRCA muta- tion status) NOVA (NCT01847274) Phase III, randomized- controlled trial -Recurrent, platinum- sensitive OC
-Any BRCA1/2
status
-2+ prior regi- mens Niraparib 300mg daily vs. placebo as maintenance PFS (months):
-Germline BRCA1/2
= 21.0 niraparib vs.
5.5 placebo
-Non-germline
BRCA1/2 = 9.3
niraparib vs. 3.3 placebo
-HRD-positive sub- group = 12.9
niraparib vs. 3.8
placebo Thrombocy- topenia, ane- mia, neutro- penia [24]
Abbreviations:
ALT = Alanine Transaminase; AST = Aspartate Transaminase; AE = Adverse Event; CI = Confidence Interval; LOH = Loss of Heterozygosity; OC = Ovarian Cancer; ORR = Objective Response Rate; PFS = Progression-Free Survival

the first to demonstrate efficacy of olaparib in patients with sporadic OC [28]. However, the ORR was higher in those with a BRCA mutation relative to sporadic OC (ORR 41% vs. 24%, respectively). A planned subgroup analysis of Study 19 by BRCA mutation status demonstrated that, al-
though olaparib was beneficial for both groups, the effect was more pronounced in patients with known BRCA muta- tions (median PFS 11.2 months for olaparib vs. 4.3 months for placebo, HR 0.18, 95% CI 0.10-0.31, p < 0.0001) com- pared to those with sporadic OC (median PFS 7.4 months vs.

5.5 months, respectively; HR 0.54, 95% CI 0.34-0.85, p = 0.0075) [32]. This PFS advantage was similar in a sub- group analysis of the 10% of patients with a somatic rather than germline BRCA mutation (HR 0.23 vs. 0.17 in somatic vs. germline BRCA mutations, respectively) [33].
Sensitivity to platinum also appears to play a role in re- sponsiveness to olaparib in patients with high grade epithe- lial OC. In a Phase I trial of 50 germline BRCA mutation carriers, the ORR differed according to platinum sensitivity, at 61%, 42%, and 15% for platinum-sensitive, -resistant, and
-refractory patients, respectively [26]. A Phase II trial dem- onstrated a more marked variation of 50-60% in platinum- sensitive compared to 4% in platinum-resistant patients [28]. Further studies may better elucidate the role of platinum sen- sitivity as a predictor of response to PARP inhibition.
PHASE 3 MONOTHERAPY TRIALS
Ongoing prospective, Phase III, Randomized-Controlled Trials (RCTs) will seek to confirm the benefit of olaparib in germline BRCA1/2 mutation carriers with OC, with a pri- mary endpoint of PFS (Table 2) [34-36]. All three of the study of olaparib in ovarian cancer (SOLO) trials utilize a dose of 300mg bid in a tablet form (four tablets daily) in- stead of the previous dosage of 400mg bid in a capsule for- mulation (totaling 16 capsules daily), with data supporting equivalent efficacy but improved tolerability [34].
SOLO-1 (NCT01844986) is the first trial to investigate the use of olaparib in newly-diagnosed OC patients. Patients who experienced a partial or complete response to adjuvant platinum-based chemotherapy are randomized 2:1 to ola- parib or placebo maintenance, with a target enrollment of
344 patients. SOLO-2 (NCT01874353) was developed to assess the therapeutic efficacy of olaparib therapy in patients with BRCA deficient, platinum sensitive recurrent ovarian cancer following complete or partial response to most recent platinum based therapy [35]. Two hundred ninety-five pa- tients with recurrent, platinum-sensitive OC, at least two prior lines of platinum-based chemotherapy, and a partial or complete response to the most recent platinum-based chemo- therapy, were randomized 2:1 to olaparib or placebo mainte- nance. Patients in the olaparib group had a significantly pro- longed median PFS of 19.1 months compared to 5.5 months in the placebo group (HR 0.30, 95% CI 0.22-0.41, p < 0.0001). Secondary endpoints of time to first subsequent therapy, PFS2, and time to second subsequent therapy were also significantly longer in the olaparib group. Together with data from Study 19, these results led to the FDA approval for olaparib as maintenance therapy in patients with platinum- sensitive OC, regardless of BRCA mutation status. SOLO-3 (NCT02282020) is the only Phase III trial investigating ola- parib monotherapy as treatment for recurrent disease. Pa- tients with recurrent, platinum-sensitive OC with two or more prior lines of platinum-based chemotherapy are ran- domized 2:1 to receive olaparib or physician’s choice stan- dard-of-care chemotherapy, with a target enrollment of 411 patients.
The potential benefit of re-exposure to PARP inhibition is being explored in a Phase IIIb, RCT of patients with recur- rent, platinum-sensitive OC and any BRCA mutation status who had previously received PARP inhibitor therapy
(OReO, NCT03106987). Patients are randomized 2:1 to ola- parib or placebo maintenance, with a target enrollment of 416.
ADVERSE EVENTS
Consideration of toxicity associated with olaparib ther- apy is critical, particularly in patients who have had multiple prior lines of chemotherapy and are unlikely to be cured. Mild Adverse Events (AEs) have been relatively common across studies, with some rare but serious AEs. In Study 19, nearly all patients experienced at least one AE, most of which were grade 1/2, with nausea (68% vs. 35%), fatigue (49% vs. 38%), vomiting (32% vs. 14%), and anemia (17% vs. 5%) being more frequent in the olaparib group. Grade 3/4 AEs occurred in 35.3% of the olaparib group and 20.3% of the placebo group, with more dose interruptions (27.9% vs. 8.6%, respectively) and reductions (22.8% vs. 4.7%, respec- tively) in the olaparib group [20]. Nausea, fatigue, vomiting, and anemia were the most common AEs in Study 42 as well, occurring in 62%, 60%, 39%, and 32% of patients, respec- tively. Grade 3/4 AEs were more frequent than in Study 19, occurring in 54% of patients. The most common were ane- mia (17%), abdominal pain (7%), and fatigue (6%), with 40% of patients experiencing a dose interruption or reduc- tion. Two patients developed acute myeloid leukemia (AML), and one developed myelodysplastic syndrome (MDS) [19]. In SOLO-2, a similar profile of mostly grade 1/2 AEs was noted and generally improved throughout treatment [37]. Anemia was the most common grade 3/4 toxicity (19% olaparib vs. 2% placebo), with others occur- ring in 10% or fewer patients in either treatment arm. Dose interruptions occurred in 4% of the olaparib group compared to 18% of the placebo group, and dose reductions in 25% and 3%, respectively. MDS and AML were rare complica- tions, occurring in four patients in each group.
HEALTH-RELATED QUALITY OF LIFE (HRQOL)
The impact of olaparib on health-related quality of life (HRQoL) was evaluated in both Study 19 and SOLO-2, with no detrimental effects identified with olaparib monotherapy. The FACT-O, FACT/NCCN Ovarian Symptom Index (FOSI), and the Trial Outcome Index (TOI) were adminis- tered at baseline and every 28 days during therapy in Study
19. Most patients (81%) reported “no change” in their HRQoL from baseline to the completion of therapy, and there were no significant differences between treatment groups at either timepoint [38]. In SOLO-2, the FACT-O TOI was used to assess HRQoL, and time without symptoms or toxicity (TWiST) was also compared between the olaparib and placebo groups. Similarly, HRQoL did not significantly decline from baseline to 12 months in either group, and TWiST was longer in the olaparib group compared to pla- cebo (13.5 months vs. 7.2 months, difference 6.3 months, 95% CI 2.9-8.6, p < 0.001) [39].
EARLY COMBINATION TRIALS
In addition to its use as monotherapy, olaparib has been studied in combination with cytotoxic chemotherapy, anti- angiogenic agents, and immunotherapy. Two Phase I/II trials have evaluated olaparib in combination with platinum-based

Table 2. Ongoing Phase III Trials of PARP Inhibitors in Ovarian Cancer.

Drug Trial Design Patient Population Regimen Primary Outcome Preliminary Data (If Any) Ref. (If Any)
SOLO1 (NCT01844986) Phase III, RCT -Newly-diagnosed OC
-PR or CR to platinum chemotherapy Olaparib 300mg bid vs. placebo as maintenance PFS
-Germline BRCA1/2
SOLO2 (NCT01874353) Phase III, RCT -Recurrent, platinum- sensitive OC
-PR or CR to recent platinum chemotherapy Olaparib 300mg bid vs. placebo as maintenance PFS PFS (months):
-Olaparib 19.1
-Placebo 5.5 [21]
-Germline BRCA1/2
Olaparib (mono- therapy) -2+ prior regimens
SOLO3 (NCT02282020) Phase III, RCT -Recurrent, platinum- sensitive OC
-Germline BRCA1/2 Olaparib 300mg bid vs. physician choice chemo- therapy as treatment PFS
-2+ prior regimens
OReO (NCT03106987) Phase IIIb, RCT -Recurrent, platinum- sensitive OC Olaparib 300mg bid vs. placebo as maintenance PFS
-Previously treated with PARP inhibitor
-Any BRCA mutation status
PAOLA-1 (NCT02477644) Phase III, RCT -Newly-diagnosed OC
-PR or CR to platinum chemotherapy with bevacizumab Olaparib 300mg bid vs. placebo as maintenance (in addition to bevaci- zumab) PFS
-Planned bevacizumab maintenance
-Any BRCA mutation status

Olaparib (com- bination therapy) COCOS (NCT02502266) Phase II/III, RCT -Recurrent, platinum- resistant OC
-Germline BRCA1/2 Four arms (as treatment):
-Olaparib alone
-Cediranib alone OS
-1-3 prior regimens -Olaparib + cediranib
-Physician choice che- motherapy
NCT02446600 Phase III, RCT -Recurrent, platinum- sensitive OC Three arms (as treat- ment): PFS
-Germline BRCA1/2 -Olaparib alone
-Any BRCA mutation status -Olaparib + cediranib
-Physician choice che- motherapy

Rucaparib ARIEL3 (NCT01968213) Phase III, RCT -Recurrent, platinum- sensitive OC
-Any BRCA mutation status
-2+ prior regimens Rucaparib 600mg bid vs. placebo as maintenance PFS PFS (months):
-BRCA mutant (germline or so- matic) with ruca- parib 16.6
-HRD-positive with rucaparib 13.6 [36]
-Intent-to-treat with rucaparib 10.8
-Intent-to-treat with placebo 5.4
Table (2) contd….

Drug Trial Design Patient Population Regimen Primary Outcome Preliminary Data (If Any) Ref. (If Any)
ARIEL4 (NCT02855944) Phase III, RCT -Recurrent OC
-Germline or somatic
BRCA1/2
-2+ prior regimens Rucaparib 600mg bid vs. chemotherapy PFS

Niraparib PRIMA (NCT02655016) Phase III, RCT -Newly-diagnosed OC
-PR or CR to platinum chemotherapy
-HRD-positive Niraparib 300mg daily vs. placebo as main- tenence PFS

Veliparib GOG 3005 (NCT02470585) Phase III, RCT -Newly-diagnosed OC
-Any BRCA mutation status Three arms:
-Chemotherapy (car- boplatin/paclitaxel) and placebo maintenance
-Chemotherapy with veliparib and placebo maintenance
-Chemotherapy with veliparib and veliparib maintenance PFS

Abbreviations:
CR = Complete Response; HRD = Homologous Recombination Deficiency; OC = Ovarian Cancer; OS = Overall Survival; PR = Partial Response; PFS = Progression-Free Survival; RCT = Randomized Controlled Trial.

chemotherapy in recurrent OC. In one small Phase Ib/II trial, patients were administered escalating doses of olaparib bid (three out of the four weeks) together with weekly car- boplatin (AUC 2) and paclitaxel (60mg/m2), with a Maxi- mum Tolerated Dose (MTD) of 150mg bid. Of 12 evaluable patients, there were four with CR and two with PR; the most common grade 3 toxicities were neutropenia, lymphopenia, anemia, fatigue, and one case of myelodysplastic syndrome [40]. In a Phase I/Ib trial of 45 BRCA1/2 mutation carriers, including 37 with OC, olaparib 400mg bid was administered days 1-7 with carboplatin (AUC 5, day 1) every 21 days, followed by the same dose of olaparib continued as mainte- nance. The objective response rate for the ovarian cancer cohort was 41%, with overall grade 3/4 AEs including neu- tropenia (42%), thrombocytopenia (20%), and anemia (16%) [41]. The addition of olaparib to platinum-based chemother- apy was shown to be of benefit in a randomized Phase II trial of 162 patients with recurrent, platinum-sensitive OC (irre- spective of BRCA mutation status) with up to three prior platinum-based regimens [42]. Patients were randomized 1:1 to one of two regimens: Olaparib 200mg bid (days 1-10) with carboplatin AUC 4 (day 1) and paclitaxel 175mg/m2 (day 1) in a 21-day cycle, followed by olaparib 400mg bid continued as maintenance or standard chemotherapy alone (carboplatin AUC 6 and paclitaxel 175mg/m2 day 1, every 21 days). The primary endpoint, PFS, was significantly pro- longed in the olaparib plus chemotherapy group relative to chemotherapy alone (median PFS 12.2 months vs. 9.6 months, respectively; HR 0.51, 95% CI 0.34-0.77, p = 0.0015), with a more pronounced benefit in those with a BRCA mutation (median PFS not reached vs. 9.7 months, HR 0.21, 95% CI 0.05-0.55). There was no OS benefit with combination therapy relative to chemotherapy alone (median OS 33.8 vs. 37.6 months, HR 1.17, 95% CI 0.79-1.73). Ad-
verse events that were at least 10% higher in the olaparib group included alopecia (74%), nausea (69%), neutropenia (49%), diarrhea (42%), headache (33%), peripheral neuropa- thy (31%), and dyspepsia (26%), and were largely grade 1/2 (with the exception of grade 3 neutropenia). Discontinuation rates due to adverse events were similar between the groups. An ongoing Phase III clinical trial (PAOLA-1, NCT02477644) is investigating the use of olaparib as main- tenance therapy in newly-diagnosed OC. Following a com- plete or partial response to adjuvant carboplatin, paclitaxel, and bevacizumab, patients are randomized to olaparib 300mg bid vs. placebo in combination with bevacizumab maintenance, with a primary endpoint of PFS and anticipated enrollment of 612.
Numerous studies have evaluated olaparib in conjunction with anti-angiogenic agents, specifically drugs that inhibit the action of Vascular Endothelial Growth Factor (VEGF). Olaparib was found to be safe in combination with bevaci- zumab, a VEGF antagonist, in a small Phase I trial, with no serious AEs or Dose-Limiting Toxicities (DLTs) noted [43]. Cediranib, a VEGF receptor antagonist, has also been found to be tolerable, with data also suggesting a benefit of combi- nation therapy. After establishing an MTD of olaparib 200mg bid in combination with cediranib 30mg daily in a Phase I study [44], the same regimen was compared to ola- parib 200mg bid alone in a randomized Phase II trial of 90 patients with recurrent, platinum-sensitive OC and any BRCA mutation status. There was a significant improvement in PFS among patients in the combination group relative to olaparib monotherapy (median PFS 17.7 months vs. 9.0 months, HR 0.42, 95% CI 0.23-0.76, p = 0.005). Grade 3/4
AEs including hypertension, fatigue, and diarrhea were more
common in the combination group, though each occurred in fewer than 20% of patients [45].

OTHER ONGOING COMBINATION TRIALS
Four Phase II/III trials are underway to try and identify patients who are likely to benefit from the combinatorial approach of olaparib with cediranib (Table 2). Two Phase II trials are investigating the efficacy of olaparib with cediranib in platinum-resistant patients, specifically by BRCA mutation status. OCTOVA (NCT03117933) randomizes germline BRCA mutation carriers to receive olaparib alone, olaparib with cediranib, or weekly paclitaxel. CONCERTO (NCT02889900) is a single-arm trial of only BRCA negative patients following at least three prior lines of chemotherapy, with administration of olaparib/cediranib combination ther- apy. With anticipated enrollment of 680 patients, COCOS is a Phase II/III randomized trial of platinum-resistant patients with four treatment arms: olaparib monotherapy, cediranib monotherapy, olaparib plus cediranib, or standard chemo- therapy alone (NCT02502266). One Phase III study includes only patients with recurrent, platinum-sensitive OC who will receive olaparib monotherapy, olaparib with cediranib, or standard chemotherapy alone, with a primary endpoint of PFS and target enrollment of 450 subjects (NCT02446600).
Additional trials are evaluating a novel combinatorial ap- proach with immune checkpoint inhibitors. The results of a Phase I dose-escalation study of durvalumab (a PD-L1 in- hibitor) with olaparib or cediranib have recently been pub- lished [46]. Durvalumab 10mg/kg every 2 weeks or 1500mg every 4 weeks was administered to twenty-six women as a doublet with escalating doses of either olaparib or cediranib.
There were no dose-limiting toxicities in the 12 women re- ceiving durvalumab and olaparib, and there was an 83% dis- ease control rate, including two partial responses and eight patients exhibiting stable disease. A Phase I/II trial is under- way evaluating tremelimumab (anti-CTLA-4) alone or in combination with olaparib in patients with persistent OC following one line of chemotherapy (NCT02485990). An- other Phase I/II trial, specific to BRCA mutations carriers with recurrent disease, is also investigating the combination of tremelimumab and olaparib, with the addition of durvalu- mab (NCT02953457).
RUCAPARIB
Rucaparib is a PARP inhibitor that was granted FDA ap- proval on December 19, 2016, for the treatment of patients with recurrent, BRCA-mutated (germline or somatic) ovarian cancer who have received two or more prior lines of chemo- therapy (US20060009517) [47] (Table 3) [48-56]. Results from two multicenter trials led to approval of rucaparib in this setting (Table 1).
PRIOR PHASE II TRIALS
Study 10 was a Phase I/II, single-arm trial that estab- lished tolerability and efficacy of rucaparib in the treatment of recurrent OC [22]. Part 1 (Phase I) included 56 patients with advanced solid tumors and established an optimal dose of 600mg bid, with manageable toxicities. In Part 2A (Phase II), 42 germline BRCA1/2 mutation carriers with recurrent,

Table 3. Recent Patents on Three FDA-Approved PARP Inhibitors.

Target Patent No. Patent title Assignee Pub. Year Ref.

Olaparib US20070179160 Use of RNAI inhibiting PARP activity for the manufacture of a medicament for the treatment of cancer University of Sheffield 2014 [48]
US20120010204 Phthalazinone derivatives Kudos Pharmaceuticals Ltd. 2014 [49]
US20060142231 DNA damage repair inhibitors for treat- ment of cancer Institute of Cancer Research, Kudos Pharmaceuticals Ltd. 2006 [50]
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Rucaparib US20060009517 Tricyclic inhibitors of poly(ADP-ribose) polyerases Agouron Pharmaceuticals, Inc., Cancer Research Campaign Tech- nology Ltd. 2006 [47]
WO2016028689 High dose strength tablets of rucaparib Clovis Oncology, Inc. 2016 [55]

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platinum-sensitive OC (with two to four prior lines of che- motherapy) were administered rucaparib 600mg bid until disease progression or toxicity. The ORR was 59.5%, with all patients experiencing an AE; the most common were fa- tigue (86%), nausea (83%), anemia (71%), elevations in as- partate and alanine transaminases (AST/ALT) (57%), or vomiting (55%). Fatigue, anemia, and elevated AST/ALT were the most frequent grade 3/4 AEs (26%, 31%, and 7%, respectively), with dose interruptions in 64% and dose reduc- tions in 69% of patients.
ARIEL2 is a Phase II, single-arm, two-part study de- signed to assess the efficacy of rucaparib based on tumor Homologous Recombination Deficiency (HRD) signature. In Part 1, 192 patients with recurrent, platinum-sensitive OC with one or more prior lines of chemotherapy were classified into one of three groups based on tumor next-generation se- quencing: BRCA mutant (germline or somatic), Loss of Het- erozygosity (LOH) high (BRCA wild-type), or LOH low (BRCA wild-type). This HRD assay was developed by Foun- dation Medicine, together with Clovis (WO2015108986) [57]. Patients were administered rucaparib 600mg bid until progression or toxicity. Median PFS was 12.8 months in the BRCA mutant group, 5.7 months in the LOH high group, and
5.2 months in the LOH low group. This difference was sig- nificant in the BRCA mutant group (HR 0.27, 95% CI 0.16- 0.44, p < 0.0001) compared to the LOH low group; a similar, though non-significant trend was seen in the LOH high group (HR 0.62,95% CI 0.42-0.90, p = 0.011) relative to the LOH low group. There was also a significant benefit in the median duration of response in the BRCA mutant group (9.2 months) and LOH high group (10.8 months) relative to the LOH low group (5.6 months). The overall AE profile was similar to that of Study 10, but with slightly less frequent grade 3/4 AEs, with anemia (21%) and elevated AST/ALT (12%) being most common [23]. An analysis of tumor biop- sies demonstrated an association between methylation of BRCA1 or RAD51C and high LOH, with promising ORR (52.4% and 75%, respectively) and PFS (7.4 months and
11.1 months, respectively). These data suggest that methyla- tion of BRCA1 or RAD51C could potentially be used as pre- dictors of sensitivity to rucaparib, pending further study [58]. ARIEL2 Part 2 specifically includes heavily pre-treated pa- tients who have received at least three prior lines of chemo- therapy, with eligibility extended to platinum-resistant and - refractory patients. Although this trial is still ongoing, pre- liminary data incorporating Parts 1 and 2 demonstrate a dif- ference in PFS by platinum sensitivity among BRCA muta- tion carriers (median PFS 12.7 months in platinum-sensitive,
7.3 months in platinum-resistant, and 5.0 months in plati- num-refractory) [59].
ONGOING TRIALS
ARIEL3 is a Phase III, double-blind RCT that was de- signed to prospectively validate the findings of ARIEL2 by evaluating patient response to treatment according to the following molecular signatures: BRCA mutant (germline or somatic), HRD-positive (including BRCA mutant and BRCA wild-type with LOH high), and intent-to-treat (all enrolled
patients) (Table 2). Five hundred sixty-four patients with platinum-sensitive, recurrent OC, and at least two prior lines of chemotherapy, were enrolled and randomized to rucaparib or placebo maintenance immediately following a complete or partial response to platinum-based chemotherapy. This trial demonstrated a significant PFS benefit of rucaparib in the BRCA mutant group (median PFS 16.6 months, HR 0.23, p < 0.0001), HRD-positive group (median PFS 13.6 months, HR 0.32, p < 0.0001), and intent-to-treat group (median PFS
10.8 months, HR 0.36, p < 0.0001) relative to placebo (me- dian PFS 5.4 months) [36]. An exploratory analysis in BRCA wild-type only demonstrated a maintained benefit of ruca- parib in both the HRD-positive (median PFS 9.7 months, HR 0.44, p < 0.0001) and HRD-negative groups (median PFS
6.7 months, HR 0.58, p = 0.0049). These encouraging results suggest that the indication for the use of rucaparib in the treatment of recurrent ovarian cancer may soon be broad- ened, with a supplemental new drug application recently submitted to the FDA for use as a maintenance therapy.
ARIEL4 (NCT02855944) is a Phase III study of rucaparib compared to chemotherapy in BRCA-mutated, recurrent OC following two or more prior lines of therapy, with a primary endpoint of PFS and target enrollment of 345 patients. Ruca- parib is also being explored in combination with atezolizumab (a PD-L1 inhibitor) in a Phase Ib trial of patients with recur- rent, platinum-sensitive OC (NCT03101280).
NIRAPARIB
Niraparib was the most recently approved PARP inhibi- tor, receiving accelerated approval by the FDA on March 27, 2017, for use in patients with recurrent, platinum-sensitive OC (at least two prior chemotherapy regimens) (Table 3). A Phase I dose-escalation trial established the recommended Phase II dose of 300mg daily, and demonstrated antitumor activity in advanced solid tumors [60]. A Phase III, double- blind, randomized controlled trial was then undertaken (NOVA), the results of which were the basis for the FDA approval of niraparib [24]. Five hundred fifty-three patients with recurrent, platinum-sensitive OC (with two or more prior platinum-based regimens) were randomized 2:1 to re- ceive niraparib or placebo as maintenance following a com- plete or partial response to the last platinum chemotherapy. A recent patent held by Myriad Genetics describes methods of assessing tumors for HR deficiency, which were used to group patients for the evaluation of response to niraparib (WO2016094391) [61]. Among germline BRCA mutation carriers, there was a significant prolongation in PFS in the niraparib group relative to placebo (median PFS 21.0 months vs. 5.5 months, HR 0.27, 95% CI 0.017-0.41, p < 0.0001).
There was a benefit among those without a germline BRCA mutation (median PFS 9.3 vs. 3.3 months, HR 0.45, 95% CI 0.34-0.61, p < 0.001) and in a prespecified analysis of the HRD-positive subgroup of the non-germline BRCA mutation group (median PFS 12.9 months vs. 3.8 months, HR 0.38, 95% CI 0.24-0.59, p < 0.0001). Patients with HRD-negative tumors were also found to have a prolonged PFS with niraparib relative to placebo (median PFS 6.9 months vs. 3.8 months, HR 0.58, 95% CI 0.36-0.92, p = 0.02). All patients

in the niraparib group experienced at least one AE, with a similar profile to other PARP inhibitors. Grade 3/4 AEs were primarily hematologic, including thrombocytopenia (34%), anemia (25%), and neutropenia (20%).
ONGOING TRIALS
Two additional trials are studying the potential role of niraparib in alternate clinical settings. QUADRA (NCT02354586) is a Phase II, single-arm trial investigating the efficacy of niraparib as treatment for patients with recur- rent, platinum-sensitive OC and BRCA-mutated or HRD- positive tumors. PRIMA (NCT02655016) is a Phase III RCT evaluating the use of niraparib as maintenance following a complete or partial response to frontline platinum-based chemotherapy in advanced stage, HRD-positive OC (Table 2). Niraparib is also being studied as combination therapy in two Phase I/II trials. ANANOVA (NCT02354131) is enroll- ing patients with recurrent, platinum-sensitive OC, with ran- domization to niraparib alone or in combination with bevaci- zumab. TOPACIO (NCT02657889) will administer escalat- ing doses of niraparib with pembrolizumab (a PD-1 inhibi- tor) in a heavily pretreated, platinum-resistant cohort.
VELIPARIB
Veliparib is a potent inhibitor of PARP1/2 that is not yet FDA-approved for use in OC, but has shown preliminary evidence of efficacy. In GOG 280, a Phase II, single-arm trial, veliparib 400mg bid was administered to 50 BRCA mu- tation carriers with recurrent OC and up to three prior lines of chemotherapy [62]. The ORR was 26%, with 35% of platinum-sensitive and 20% of platinum-resistant patients responding to therapy. Gastrointestinal AEs were similar to olaparib, but grade 3/4 hematologic AEs were infrequent (0- 2%). Other trials have investigated veliparib as combination therapy. A Phase I trial of veliparib plus whole abdominal radiation in patients with peritoneal carcinomatosis (includ- ing 18 OC patients) demonstrated tolerability but only a 3% ORR [63]. Veliparib combined with cyclophosphamide was evaluated in a randomized Phase II trial of patients with BRCA-mutated advanced solid tumors [64]. The addition of veliparib compared to cyclophosphamide alone did not im- prove the PR rate (11.8% vs. 19.4%, respectively) or median PFS (2.1 months vs. 2.3 months, respectively; p = 0.68). GOG 9923 was a Phase I trial that evaluated veliparib with frontline platinum-based chemotherapy (IV carboplatin and paclitaxel, or IV/IP cisplatin and paclitaxel), as well as bevacizumab [65]. Currently, in a Phase III, three-arm RCT of newly-diagnosed OC patients, carboplatin and paclitaxel are administered with or without veliparib therapy, followed by veliparib or placebo maintenance (GOG 3005, NCT02470585) (Table 2).

TALAZOPARIB
Talazoparib is a PARP inhibitor with antitumor activity at significantly lower concentrations than other drugs in this class [66]. A Phase I trial that included 23 patients with OC, of whom 17 had germline BRCA mutations, established a maximum tolerable dose of 1mg daily. In an expansion co-
hort with 12 BRCA-mutated OC patients, there was an ORR of 42% [67]. Toxicities were somewhat milder than other PARP inhibitors, with grade 1/2 nausea and fatigue each occurring in less than 40% of patients, and grade 3/4 AEs limited to anemia (23%), thrombocytopenia (18%), and neu- tropenia (10%). Talazoparib was investigated together with either temozolomide or irinotecan in a Phase I dose- escalation trial, which demonstrated partial responses in 4/7 (57%) patients with platinum-resistant OC [68]. Interest- ingly, response was correlated with an HRD score of 42 or greater as assessed by next-generation sequencing of tumors. Grade 3/4 AEs were mostly hematologic, and this combina- tion was generally well-tolerated. Phase II trials were initi- ated to assess talazoparib monotherapy or in combination with temozolomide in OC patients with prior PARP inhibi- tion treatment, but are no longer open.
CONCLUSION
In an era of molecular therapy, PARP inhibitors have emerged as an exciting new option for patients with ad- vanced stage, recurrent ovarian cancer. Ongoing clinical tri- als and the completion of novel translational objectives di- rected at predicting response will continue to inform patient selection. Although both drug resistance and high cost of therapy remain targets for improvement, PARP inhibitors, both as single agents and in combination with other drugs, represent a new treatment paradigm.
CURRENT & FUTURE DEVELOPMENTS
Predicting PARP Responsiveness
With a multitude of ongoing studies in different patient populations and clinical settings, it is likely that the indica- tions for PARP inhibitors in OC will continue to expand. Yet the question of accurately predicting who will benefit most from this therapy remains unanswered. Germline and so- matic BRCA1/2 mutations have thus far been used to predict, to some extent, who may respond to PARP inhibition; how- ever, more sensitive and specific biomarkers are needed. HRD assays are currently being developed as a means of assessing genomic instability characteristic of the “BRCAness” phenotype, by determining the extent of LOH, Telomeric Allelic Imbalance (TAI), and large-scale state transitions in DNA [69-71]. Myriad Genetics has developed the MyChoice HR deficiency assays, which incorporates all three of these HRD scores [72] (WO2016094391) [61] (Ta- ble 4) [77-84]. Foundation Medicine, together with Clovis, has utilized a LOH threshold of 14% to define “LOH-high” patients within the BRCA wild-type subgroup in ARIEL2 (WO2015108986) [57]. A high correlation with response to rucaparib was noted, and a planned post hoc analysis has already “refined” this cutoff to be more predictive of im- proved PFS with rucaparib [73].
Other recent patents reflect an ongoing effort to identify biomarkers to predict either response to or resistance to PARP inhibitors. Richardson and colleagues developed a Global Chromosomal Aberration score (GCAS) which incorporates Copy Number Alterations (CNA) in addition to detecting

Table 4. Recent Patents on PARP Inhibitor Use as Combination Therapy and the Development of Novel Biomarker Assays.

Target Patent No. Patent title Assignee Pub. Year Ref.

PARP inhibitors as combination ther- apy WO2017031445 Combination therapy for cancer treatment Merrimack Pharmaceuticals, Inc. 2017 [77]
WO2012016876 Therapeutic combination comprising a PARP-1 inhibitor and an anti-neoplastic agent Nerviano Medical Sciences S.R.L. 2013 [78]
WO2017077326 Combination of an inhibitor of PARP with an inhibitor of GSK-3 or DOT1L King’s College London 2017 [79]

Development of biomarker assays WO2016018089 Novel biomarker for predicting sensitiv- ity to PARP inhibitor, and use thereof The Asan Foundation 2016 [80]
US20130224312 Methods and materials for assessing responsiveness to PARP inhibitors and platinating agents Mayo Foundation for Medical Education and Research 2013 [81]
WO2014138101 Gene signature to predict homologous recombination (HR) deficient cancer Board of Regents, The University of Texas System 2014 [82]
WO2013182645 Methods for detecting inactivation of the homologous recombination pathway (BRCA1/2) in human tumors INSERM 2015 [83]
WO2014205105 Biomarkers of response to inhibition of poly-ADP ribose polymerase (PARP) in cancer The Regents of the University of California 2016 [84]

LOH, TAI, and LST (US20170037478) [74]. Another patent describes the detection of a Single Nucleotide Polymorphism (SNP) in the PARP1 gene that may confer resistance or sensi- tization to PARP inhibition (WO2016073298) [75]. Mach describes a novel imaging method whereby radiolabeled PARP1 inhibitors are combined with Positron Emission To- mographic (PET) imaging to detect tumoral PARP activity and the efficacy of PARP inhibition, as a guide for drug dos- ing (WO2015103526) [76].
Resistance to PARP Inhibition
Another challenge to overcome is acquired PARP resis- tance after exposure to drug. Numerous mechanisms have been identified for inherent or acquired resistance. One is the up regulation of genes encoding p-glycoprotein efflux pumps, which over time decrease intracellular drug levels [85]. In a murine breast cancer model, a PARP inhibitor (AZD2281) was administered with initial tumor shrinkage that then plateaued, correlating with a significant increase in the expression of p-glycoprotein efflux pumps. Co- administration of p-glycoprotein inhibitor, tariquidar, re- versed this resistance.
Restoration of HR can also be responsible for the de- velopment of resistance to PARP inhibitors, through a secondary mutation in a protein critical to the HR pathway. In tumors harboring a BRCA1/2 mutation, a new somatic mutation or deletion can restore the open reading frame of the gene, allowing for translation of a functional BRCA protein [86]. Similarly, in ARIEL2 Part 1, secondary somatic mutations in RAD51C and RAD51D- both integral to HR- were associated with resistance to PARP inhibition [87]. The genetic profile of pre-treatment tumor samples
genetic profile of pre-treatment tumor samples was com- pared to that of post-treatment biopsies in 12 patients who progressed on therapy. Five of these patients had a delete- rious mutation in RAD51C or RAD51D on the initial bi- opsy, with post-progression biopsy revealing a secondary mutation that restored the open reading frame of the corre- sponding gene. Loss of function of 53bp1, a protein in- volved in NHEJ, may restore HR pathway function and has been correlated with PARP inhibitor resistance in BRCA1- mutated tumors [86].
Expression of Schlafen 11 (SLFN11) has recently been identified as a marker of PARP inhibitor resistance in a manner distinct from the previously discussed mechanisms. In two separate analyses of the publically-available Genom- ics of Drug Sensitivity in Cancer (GDSC) dataset and the National Cancer Institute (NCI)-60 genomic database, SLFN11 was highly correlated with sensitivity to olaparib, rucaparib, and veliparib, as well as talazoparib [88, 89]. Mu- rai et al conducted a series of experiments suggesting that, instead of altering drug penetration or restoring HR activity, SLFN11 induces prolonged S-phase arrest and induces apop- tosis in cells treated with talazoparib, thus conferring sensi- tivity [89]. In vitro assays using genetic knockout or knock- down of SLFN11 demonstrate a significant increase in resis- tance to PARP inhibitors in small cell lung cancer [88, 90], as well as in cell lines derived from prostate cancer, leuke- mia, and Ewing’s sarcoma that exhibit high baseline expres- sion of SLFN11 [89]. These data are supported by patient- derived xenograft models, demonstrating that high tumor expression of SLFN11 (assessed by immunohistochemical staining) was correlated with significant tumor regression in numerous cancer types [88-90]. Interestingly, Lok et al. de-

tected a bimodal distribution in SLFN11 expression in treat- ment-naïve patient tumor samples, suggesting the potential exploration of SLFN11 as a predictive biomarker for PARP inhibitor sensitivity [88].
Currently, methods are being developed in an attempt to reverse resistance to PARP inhibitors. Regarding tumors affected by low SLFN11 expression, Murai et al. demon- strated that inhibition of ATR, a mediator of the DNA dam- age response upon which SLFN11-deficient cells rely for survival, can reverse resistance to PARP inhibitors [89]. In vitro studies have demonstrated that histone deacetylase in- hibitors enhance sensitivity of breast cancer cells to PARP inhibition [91]. An inhibitor of heat shock protein 90 (HSP90), which prevents ubiquitin-proteosome degradation of many oncogenes, has shown synergy with PARP inhibitor administration in a preclinical model of PARP inhibitor- resistant ovarian cancer [92]. Other pharmacologic methods for reversing PARP inhibitor resistance are being investi- gated, targeting proteins such as cyclin-dependent kinase 1 and BARD1 that interact closely with BRCA proteins [93].
Cost Effectiveness
for cost reduction, while maintaining patient access to this exciting class of drugs.
CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
Ramez N. Eskander has received speaker compensation from AZ Oncology, Genentech, and Clovis Oncology.
Kristin N. Taylor has no conflict of interest related to the content of this article.
ACKNOWLEDGEMENTS
Declared none.
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