American Journal of Hematology / Oncology®
New Biologic Frontiers in Ovarian Cancer: Olaparib Update

Rebecca A. Previs, MD, Heather J. Dalton, MD, and Robert L. Coleman, MD

Abstract

Poly (ADP-ribose) polymerase (PARP) inhibition was first introduced as a cancer-targeting strategy in 2005 and has made rapid clinical progression, culminating in the Food and Drug Administration approval of olaparib as a fourth-line-and-beyond treatment in relapsed BRCA-mu- tated ovarian cancer in December 2014. This approval followed exciting phase 1/2 data showing anti-tumor efficacy in patients with ovarian cancer, particularly in BRCA-deficient and platinum-sensitive populations.
This article will review the early clinical investigation of olaparib, emerging phase 2 and 3 data, and future direc- tions, including forthcoming clinical trials and methods to predict response and expand the populations eligible to receive this innovative biologic therapy.

AJHO. 2016;12(11):14-22

Introduction

Poly (ADP-ribose) polymerase (PARP) inhibition was first intro- duced as a novel cancer-targeting strategy in 2005, following the publication of preclinical work showing activity in BRCA-mu-  tated tumor cells. Compared with wild-type cells, BRCA1- and BRCA2-deficient cells were up to 1000-fold more   sensitive to PARP inhibition.1 In vivo, the growth of BRCA2-deficient tumors was decreased by PARP inhibitors, the first demonstra- tion that inhibition of a DNA repair mechanism could be used    to target cancer cells.2  These studies highlighted the application   of synthetic lethality as a potentially effective anticancer therapy and inspired further clinical   investigation.

PARP inhibitors are now known to work through a variety of mechanisms, in addition to inducing synthetic lethality.1,2 PARP inhibition stimulates nonhomologous end joining (NHEJ) selectively in homologous repair-deficient cells.3 This is achieved  via inhibition of DNA-dependent protein kinase substrates, leading to genetic instability, chromosome rearrangement, and   cell death. PARP inhibitors have also been shown to trap PARP-   1 and PARP-2 on DNA, leading to PARP-DNA complexes.4 This concept, known as “PARP trapping,” is thought to be    responsi- ble for the synergism seen with PARP inhibition and alkylating agents and does not occur with all PARP   inhibitors.

Since their introduction, PARP inhibitors have been studied in many BRCA-deficient cancers, including ovarian cancer, where  they have had notable success. The most extensively studied   PARP inhibitor in ovarian cancer is olaparib, an orally available compound with activity against PARP-1 and PARP-2. The recent FDA approval of olaparib in relapsed ovarian cancer brings this drug class to the forefront of new anticancer therapy in this  disease. This review will update our previous review5 and discuss the emerging clinical trial data and future directions of research   on PARP inhibitors and ovarian  cancer.

Phase 1 Investigation

Early phase 1 investigation of olaparib confirmed activity in BRCA-mutated breast and ovarian cancers.6 Sixty patients with  solid tumors refractory to standard therapy were enrolled, including 21 patients with ovarian cancer and 9 patients with breast cancer. The majority of patients had received at least 4   prior lines of treatment. Nineteen BRCA1 and BRCA2 mutation carriers were evaluable following treatment, 9 of whom had a partial response (PR) or complete response (CR) to    olaparib by Response Evaluation Criteria in Solid Tumors (RECIST;     8 patients with ovarian cancer and 1 with breast cancer).7 Of   the patients with ovarian cancer, 6 had a decrease of 50% or more in their CA125 levels. Twelve of the 19 patients (63%) with BRCA1/2  mutation derived clinical benefit, defined by    a decrease in tumor markers, radiographic response, or   stable disease (SD) for 4 or more months. Further, olaparib was found   to have an acceptable side-effect profile, with grade 1 and 2 nau- sea and fatigue being the most commonly experienced adverse events (AEs).

In a confirmatory trial, patients with BRCA1/2-mutated ovarian cancer were treated with olaparib as a part of a dose-es- calation  and  expansion  study.8  This  included  50  patients,  48 of whom had BRCA1 or BRCA2 mutation, 1 with a missense BRCA2 mutation of unclear significance, and 1 with a    strong family history of BRCA1/2 cancers who declined testing. Of the patients enrolled, 13 had platinum-sensitive disease, 24 had plat- inum-resistant  disease,  and 13 had platinum-refractory disease (progression of disease while receiving platinum chemotherapy). The majority of patients (39 of 50) received olaparib 200 mg   twice daily as a part of the expansion cohort. The   11  patients in the escalation group received olaparib at dosages ranging   from 40 mg daily up to 600 mg twice daily. Of the 50 patients,   4 were not evaluable and an additional 8 had no measureable disease by RECIST. Partial response or CR was seen in 14 patients (28.0%; 95% CI, 16.2-42.5). An additional 3    patients had SD for greater than 4 cycles (6.0%; 95% CI, 1.3-16.5). Of  the patients with platinum-sensitive disease,  61.5%  responded  to treatment, as measured by RECIST or The Gynecological Cancer InterGroup (GCIG) criteria. Patients with platinum-re- sistant disease saw a 41.7% response rate, while no RECIST responses were observed in the platinum-refractory group. Two patients in this cohort did have response by GCIG criteria and    1 patient had SD. This trend toward decreasing response rates with decreasing platinum sensitivity was significant, although   the responses seen in the platinum-resistant/refractory   groups were better than those seen in many other studies of this cohort.

Early Phase 2 Studies in Ovarian Cancer

Following the activity demonstrated in the phase 1 study, a proof-of-concept phase 2 study was initiated.9 This multicenter trial enrolled BRCA1 and BRCA2 mutation carriers with recur- rent ovarian cancer and at least 1 previous line of therapy to continuous olaparib at either 100 mg twice daily, demonstrated   to be pharmacodynamically active, or 400 mg twice daily, the maximum tolerated dose in the initial phase 1 study, until dis-  ease progression.6 Platinum status was also assessed at the time    of enrollment.  The primary endpoint  was  objective response rate (ORR). Fifty-eight patients were enrolled, with 1 patient  death prior to treatment initiation, leaving 57 patients available for analysis, including 40 with BRCA1 mutations and 17 with BRCA2 mutations. The ORR in the 400 mg cohort was 33%   (11 of 33 patients; 95% CI, 20-51), with 2 CRs and 9 PRs.An additional 36% of patients had SD and a median duration of
response (DoR) of 290 days. In contrast, the ORR in the 100-mg cohort was 13% (3 of 24 patients; 95% CI, 4-31) with no CRs. Seven patients (29%) had SD. The median progression-free survival (PFS) was 5.8 (95% CI, 2.8-10.6) versus 1.9 (95% CI, 1.8-3.6) months in the 400-mg and 100-mg cohorts,   respectively.
The authors concluded that olaparib had antitumor activity in    a heavily pretreated population of patients with BRCA1- and BRCA2-mutated  ovarian  cancer.  Further,  olaparib  was  noted to have activity in platinum-sensitive and   platinum-resistant disease, with 38% (5 of 13 patients) and 30% (6 of 20 patients) responding  to  treatment,  respectively.  Importantly,  this  trial was not randomized, and the lower-dosage cohort had poorer prognostic features,  perhaps  confounding  the apparent dose-de- pendent activity. This and other subsequently presented phase 2 studies are summarized in the  Table.

An additional phase 2 study investigated olaparib versus pegylated liposomal doxorubicin (PLD) as monotherapy in re- lapsed BRCA1/2-mutated ovarian cancer with an interval of less than 12 months after previous platinum-based chemotherapy.10 This study also sought to determine the most appropriate dos-    age  of olaparib,  either  200 mg or  400 mg twice daily, although  it was not powered to detect a difference between these groups. PFS was the primary outcome of this multicenter, randomized prospective trial, in which 97 patients were enrolled in a 1:1:1 ratio to olaparib at 200 mg twice daily or 400 mg twice daily, or to PLD at 50 mg/ m2 every 28 days. Crossover from PLD to olaparib 400 mg twice daily was allowed at the time of disease progression. Median PFS was 6.5 months (95% CI,    5.5-10.1), 8.8 months (95% CI, 5.4-9.2), and 7.1  months (95%   CI, 3.7-10.7) for the olaparib 200 mg, olaparib 400 mg, and PLD groups, respectively. There was no significant difference between either of the dosing cohorts of olaparib and PLD. The 31%     ORR of patients receiving olaparib 400 mg was similar to previ- ously published data.6,9 While 50% of the patients enrolled were classified as platinum-resistant, response rates were not reported   by platinum status. Notably, the PLD group performed better   than expected, with a PFS of 7.1  months compared with a PFS    of 4 months in a previously published large prospective trial of patients with relapsed ovarian cancer with unknown BRCA1/2 mutation status.11 Subsequently published data suggest that BRCA1/2 mutation carriers may derive more clinical benefit   from  anthracycline-based chemotherapy than nonselected  patients, as these compounds may capitalize on homologous  repair deficiency.12,13

BRCA Status and Response to Olaparib

Kaufman et al14 published the results of a large, multicenter, nonrandomized phase 2 trial in recurrent BRCA1/2 mutant    solid tumors, including breast, ovarian, prostate, and pancreatic cancer,  among  others.  Enrolled  patients  with  ovarian  cancer were required to be platinum-resistant. The primary endpoint   was tumor response rate by RECIST, with secondary endpoints   of ORR, PFS, and DoR. A total of 298 patients were enrolled to receive oral olaparib 400 mg twice daily until disease progres-   sion, including 193 with epithelial ovarian, primary peritoneal,    or fallopian tube cancer. BRCA1 germline mutations made up 77% of this cohort, while 23% carried BRCA2 mutations. The tumor response rate was 26.2% (95% CI, 21.3-31.6) in patients  with ovarian cancer, with 40.4% (95% CI, 33.4-47.7)    achieving SD. Median PFS was 7.0, 3.7, 4.6, and 7.2 months in the ovari- an, breast, pancreatic, and prostate cancer groups, respectively. Importantly,  ovarian  cancer  response  rates  were  similar  to those seen in previous studies, despite the   platinum-resistant patient population, suggesting that the mechanisms of platinum resistance may not always confer resistance to PARP inhibi-  tion.9,10 This study highlights the activity of olaparib in a variety of germline BRCA-mutated solid tumors and helped  to pave   the way for FDA approval of this agent in fourth-line, relapsed, BRCA-mutated ovarian cancer on December 19, 2014. An    up- date to the long term safety and efficacy of this study population has recently been reported. ORR was 34% (46/137) and median DoR was 7.9 months (95% CI, 5.6-9.6). ORR was 30% in platinum-resistant tumors. Median  DoR  for  platinum–sensitive and platinum-resistant tumors was 8.2 (95% CI, 5.6-13.5) and 8 months (95% CI, 4.8-14.8), respectively. Three percent had an adverse outcome, which was death. No new safety signals were identified.15

The role of BRCA mutations in predicting response to olapa- rib in advanced high-grade serous ovarian cancer or    undiffer- entiated ovarian cancer and triple-negative breast cancer was assessed in a phase 2 multicenter study by Gelmon et al.16  In     this nonrandomized, open-label trial, patients were stratified ac- cording to BRCA mutation status and received olaparib 400 mg twice daily. Ninety-one patients were enrolled, with 90 receiving treatment,  including 17  patients with BRCA1/2  mutations and 46 without mutations. The primary outcome of ORR was not met in the breast cancer cohort. Of the 63 patients with ovarian cancer who were evaluable, objective responses were  seen in 7 of 17  patients (41%; 95% CI, 22-64) with BRCA1   or
BRCA2 mutations and 11 of 46 patients (24%; 95% CI 14–38) without mutations. Post-hoc analyses revealed that 50%   (10 of 20 patients) with BRCA1/2 wild-type    platinum-sensitive ovarian cancer had an objective response, while 60% (3 of 5)      of patients with platinum-sensitive BRCA1/2-mutated disease  had a response. Responses were seen in 4 patients (33%) with platinum-resistant BRCA1/2-mutated ovarian cancer compared with only 1 (4%) of those in the BRCA1- or BRCA2-negative cohort. Although  activity was  seen in both  platinum-sensitive and platinum-resistant cohorts, a greater response was observed  in the platinum-sensitive cohort. While the majority of patients with BRCA mutations were noted to have a response, this study importantly demonstrates the activity of olaparib in patients without germline BRCA1 or BRCA2   mutations.

Olaparib in Platinum-Sensitive Ovarian Cancer

Based on previous studies suggesting a greater response to    olaparib  in  patients  with  platinum-sensitive  ovarian  cancer, several  trials  selectively  enrolled  this  population.8,16  One  such trial investigated olaparib alone versus the combination of   olaparib plus cediranib.17 Cediranib is an oral tyrosine kinase inhibitor  with  anti-angiogenic  effects  mediated  through  VEG- FR1, VEGFR2, and VEGFR3, which has demonstrated activity in relapsed  ovarian  cancer.17,18  Ninety-three  patients  were  assessed for eligibility, with 3 patients not qualifying. The remaining  patients were randomized to receive either olaparib alone at 400   mg twice daily or olaparib plus cediranib (200 mg twice daily and  30 mg daily, respectively). Patients were also stratified according    to their BRCA status (mutation carrier, noncarrier, or unknown). Forty-six patients received olaparib alone; while 44 received combination treatment. Similar to previous studies, olaparib monotherapy resulted in a PFS of 9.0 months (95% CI, 5.7-    16.5), whereas the combination group saw a PFS of 17.7 months (14.7–not reached; hazard ratio [HR], 0.42; 95% CI,    0.23-0.76; P = .005).9,14 Objective response rates of 47.8% and 79.6% were  seen in the olaparib-only and olaparib-plus-cediranib groups, respectively. Six of 7 CRs occurred in patients with BRCA-mutat-   ed disease. A post hoc analysis of PFS and ORR data revealed a greater response to combination therapy in patients with BRCA wild-type disease and in those with unknown status. While this warrants further investigation, this analysis should be interpreted with caution, as the BRCA-mutated group may have performed better than expected with a PFS of 16.5 months. The combi-   nation group more frequently experienced grade 3 diarrhea,   fatigue, and hypertension, with 75% of the cohort requiring   dosage reductions.  This study provides the first   investigation
into PARP inhibition in combination with an anti-angiogenic agent, and has paved the way for phase 3 trials (NCT02446600, NCT02502266).

Olaparib has demonstrated activity in combination with chemotherapy in recurrent, platinum-sensitive ovarian cancer.19     In a phase 2, randomized study, 162 eligible patients were   enrolled 1:1 to olaparib plus carboplatin and paclitaxel followed  by olaparib monotherapy as maintenance or carboplatin    and paclitaxel alone. The olaparib-plus-chemotherapy group received olaparib 200 mg twice daily on days 1 to 10 of a 21-day cycle plus paclitaxel (175 mg/m2) and carboplatin (area under the curve [AUC] 4 mg/mL/minute) on day 1 for 6 cycles, followed by maintenance olaparib 400 mg twice daily until disease progres-  sion. The chemotherapy group received paclitaxel (175 mg/m2)   and carboplatin (AUC 6) on day 1 of a 21-day cycle for 6 cycles     or disease progression. Thirty-eight percent of patients carried BRCA1 or BRCA2 mutations and were balanced between   groups.

The primary endpoint was PFS; overall survival (OS) served as     a secondary endpoint. The majority of patients (75%) in both groups received 6 cycles of treatment. More AEs were reported   in patients receiving olaparib plus chemotherapy, with 53 of 81 patients (65%) experiencing grade 3 or higher AEs compared  with 43 of 75 patients (57%) receiving only chemotherapy. The addition of olaparib to standard chemotherapy significantly im- proved PFS compared with chemotherapy alone, with a median of 12.2 (95% CI, 9.7-15.0) versus 9.6 months (95% CI,    9.1-
9.7), respectively (HR, 0.51; 95% CI, 0.34-0.77; P = .0012).    The improvement in PFS was even more pronounced in patients with BRCA mutations, where PFS was not reached in this group after    a median follow-up of 9.8 months (HR, 0.21; 95% CI, 0.08-0.55;    P = .0015). While there was no significant difference in OS be- tween the groups by treatment cohort or BRCA status, explorato-   ry analyses showed an improvement in time to first subsequent therapy or death favoring the combination therapy with olaparib (HR = 0.60; 95% CI, 0.42-0.86; P = .0053). This has been pro- posed to reflect post-progression efficacy of maintenance therapy with olaparib. A phase 3 ongoing study includes NRG GY004, which is comparing single agent olaparib or the combination of cediran-   ib and olaparib to standard platinum-based chemotherapy in women with recurrent platinum-sensitive ovarian carcinoma (NCT02446600).  In  this  study,  patients  are  randomized  1:1:1 to either olaparib monotherapy or cediranib and olaparib combination or platinum-based chemotherapy. Platinum-based chemotherapy options may include carboplatin and paclitaxel, carboplatin and gemcitabine, or carboplatin and pegylated lipo- somal doxorubicin.

Olaparib in Platinum-Resistant Ovarian Cancer

While response to olaparib has been correlated with platinum sensitivity, multiple studies have demonstrated activity in pa-    tients with platinum-resistant ovarian cancer.8,16 Audeh et al9 saw ORRs of 30% (6 of 20 patients) in this cohort. Other studies    have shown ORRs ranging from 33% to 42% in platinum-resis-  tant populations.8,16 Kaufman et al14 specifically enrolled patients with platinum-resistant BRCA1/2-mutated ovarian cancer in a  phase 2 study and found an ORR of 26.2%, with 40.4% of pa-  tients achieving SD. Median PFS was 7 months, comparing favor- ably with other studies in platinum-resistant ovarian    cancer.20,21 Further clinical investigation of olaparib in platinum-resistant ovarian cancer is  warranted. Early phase 1 studies are evaluating a newer PARP inhibitor, veliparib, in combination with pegylated liposomal doxorubicin, carboplatin, in combination with bevacizumab.22 This NRG Oncology/Gynecologic  Oncology  Group  study’s  objective  was to determine the maximum tolerated dose and dose-limiting toxicities of this combination. Patient received PLD (30    mg/m2, IV) and carboplatin (AUC 5, IV) on day 1 with veliparib on days    1 to 7 (intermittent) or days 1 to 28 (continuous). A 3 + 3 design was used in the dose escalation phase. Once the maximum toler- ated dose was determined, a cohort of six patients were enrolled    in each regimen with bevacizumab (10 mg/kg on days 1 and 15)   to determine the feasibility. A total of 27 patients were treated at three dose levels and dose-limiting toxicities were noted in six patients, which included four patients with grade 4 thrombocy- topenia and three patients with neutropenia greater than seven days. The maximum tolerated dose of veliparib was determined    to be 80 mg twice daily for both arms and myelosuppresion was  the  primary dose-limiting  toxicity.  Twelve  patients  were  treated at this dose with the addition of bevacizumab, and nine patients experienced dose-limiting toxicities, which included thrombocy- topenia, prolonged neutropenia, hypertension, and one patient experienced sepsis. Previous studies have hypothesized that the continuous dosing of veliparib would be the best dosing strategy for patients with BRCA mutations, while intermittent dosing   may suffice when using PARP inhibition for chemo-sensitization in patients with homologous recombination  deficiency.23  Signif- icant hematologic toxicity was encountered in this early study,    but  warrant  further research pre-clinically.

PARP Synergy With Anti-Angiogenic Therapies

Mounting pre-clinical evidence has suggested a synergistic or combinatory effect with PARP inhibitors when combined with anti-angiogenic inhibitors.24 The mechanism for this rationale in- cludes the downregulation of homologous recombination repair genes in hypoxic setting, which ‘resests’ PARP inhibitor sensi-   tivity. In addition, BRCA1 and BRCA2 have been found to be downregulated in ovarian cancer cells with VEGF    inhibition.25,26 The safety and tolerability in a phase 1 study of bevacizumab    in combination with another PARP inhibitor in development, niraparib, in platinum-sensitive ovarian cancer patients, the ENGOT-OV24/AVANOVA1 trial.27 This single-arm study evalu- ated patients in a 3 + 3 design. The patients received fixed dose bevacizumab (15 mg/kg IV every 21  days) with dose escalation    of niraparib (100, 200, 300 mg orally daily). The objective was     to establish the maximum tolerated dose and dose-limiting toxicities. Twelve patients were enrolled to three dose    levels, of which three had a germline BRCA2 mutation. Commonly  related toxicities included hypertension, anemia, thrombocytope- nia, fatigue, constipation and nausea. The recommended    phase 2 dose established was bevacizumab 15 mg/kg every 21 days with niraparib 300 mg orally daily. A phase 2 trial is currently ongo-    ing (NCT02354131).

PARP Inhibitors As a Maintenance Strategy

Ledermann  et  al28  investigated  olaparib  as  a  maintenance  strat- egy in relapsed, platinum-sensitive patients in a randomized, multi-center phase 2 trial. Patients were required to have received    2 or more platinum-based chemotherapy regimens and to have   had a PR or CR with their most recent platinum therapy. Both patients  with  BRCA-mutant  and  wild-type  disease  were  eligible for enrollment. A total of 265 patients were randomized, includ-  ing 136 to the olaparib-400-mg-twice-daily  cohort and 129   to
the placebo arm. The primary endpoint of PFS was noted to be significantly longer in patients receiving olaparib maintenance than those receiving placebo at 8.4 months versus 4.8 months (HR, 0.35; 95% CI, 0.25-0.49; P <.001). At the cutoff point for data analysis, the median exposure to olaparib was 206.5 days compared with 141 days for placebo. More AEs were seen in patients receiving olaparib, with the most common side effects being nausea, vomiting, and   fatigue.

A subsequently published preplanned retrospective analysis  of the original study assessed the efficacy of olaparib    mainte- nance according to BRCA mutation status.29 Of the 136 patients originally  randomized to the olaparib maintenance arm, 74  of   131 patients (56%) with known mutation status carried germline BRCA mutations, while 62 of 123 (50%) had tumor mutations    of BRCA. Patients with a BRCA mutation receiving olaparib had   a significantly longer PFS at 11.2 months compared with 4.3 months in those with a BRCA mutation receiving placebo (HR, 0.18; 95% CI, 0.10-0.31; P <.0001). No OS differences were not-  ed between the groups by treatment or BRCA mutation   status.

In the previously presented study by Oza et al,19 olaparib was administered with chemotherapy followed by maintenance olapa- rib. No separation in the PFS curves was seen during concomi-  tant use relative to control chemotherapy; however, the curves separated significantly during the maintenance  phase.  Although the study was not designed to assess the contributions of each treatment  phase,  the late separation  of the PFS curves seen in  the trial suggests the maintenance phase to be the most import-    ant contributor to the improvement in PFS. This finding led the authors to conclude that olaparib plus chemotherapy does not provide any advantage over olaparib maintenance   alone. The findings from these trials have led to the development     of 2 phase 3 trials investigating olaparib maintenance. SOLO-1 (NCT01844986) is a randomized, double-blind, placebo-con- trolled, multicenter trial investigating olaparib maintenance in advanced  BRCA-mutated ovarian  cancer following completion of first-line platinum chemotherapy. The primary endpoint   is PFS, with secondary endpoints of OS and quality of life, among others. Planned accrual is 397 patients, and no longer recruiting patients. Patients randomized to the treatment arm will receive olaparib 300 mg twice daily for up to 2 years or until disease progression.

SOLO-2 (NCT01874353) is a randomized, double-blind, pla- cebo-controlled, multicenter phase 3 trial investigating olaparib maintenance in platinum-sensitive, recurrent BRCA-mutated ovarian cancer. Patients must have received 2 prior platinum-   based chemotherapy regimens, with disease progression greater  than 6 months after completion of their last dose of platinum chemotherapy. Randomization must occur within 8 weeks of completion of platinum-based chemotherapy. The olaparib maintenance arm will receive olaparib 300 mg twice daily until disease progression. PFS is the primary objective. Accrual for this trial  has completed.

The effectiveness of olaparib is being compared with chemo- therapy in recurrent, platinum-sensitive germline BRCA-mutated ovarian cancer in the SOLO-3 trial (NCT02282020). In this    phase 3 study, patients are randomized to either olaparib 300 mg twice daily or single-agent, non-platinum-based chemotherapy, as chosen by the treating clinician. Patients must have    completed
2 previous lines of platinum-based chemotherapy. The primary endpoint is PFS. This trial is open and currently recruiting patients. Of note, SOLO-1, SOLO-2, and SOLO-3 utilize the tablet form of olaparib rather than the capsule form studied in the phase 1 and 2 trials. While the dosage of 300 mg is lower than that used in many trials, it has higher bioavailability and provides  equivalent  drug exposure.

Resistance to PARP Inhibition

Despite their clinical promise, resistance to PARP inhibition remains a challenge to the implementation of these agents.  Acquired resistance to both platinum-based chemotherapy and PARP inhibition has been linked to secondary mutations in BRCA2 that restore the wild-type reading frame.30 Cisplatin-re- sistant cells were found to acquire a variety of mutations, all of which restored the wild-type BRCA2 reading frame and conferred resistance to both cisplatin and PARP inhibition. In an evalu-   ation of recurrent BRCA2-mutated patient samples originally  treated with cisplatin, those resistant to cisplatin were    found to have reverted to a wild-type BRCA2 phenotype. Ashworth31 confirmed that resistance to PARP inhibition could be acquired through deletion of a BRCA2 mutation. Additional mechanisms include increased activity of BRCA1 or BRCA2 variants encoded  by hypomorphic alleles and rescue of DNA end-resection in BRCA1-deficient tumors through loss of    53BP1.32 Resistance to PARP inhibition has also been shown to develop through increased expression of P-glycoproteins in BRCA1-mutated breast cancers.33 This resistance was overcome with    administration of 6-thioguanine (6TG), which in the case of BRCA1-mutated cancer probably results from it being a poor substrate for P-gly- coprotein. However, it was also noted that 6TG was effective    in inducing cell death among PARP inhibitor-resistant BRCA2-mu- tated tumors harboring a functional BRCA2 reversion. Detailed investigation suggested that 6TG induces both mismatch-de- pendent and -independent DNA damage requiring homologous recombination repair. 6TG has been proposed as a potential strategy to combat acquired resistance to PARP    inhibition.

Homologous Recombination Deficiency in Non-BRCA Mutant Patients

Patients with non-germline mutations in BRCA but have homol- ogous recombination deficiency due to defects in this DNA dam- age pathway have been investigated. The ARIEL2 trial    sought
to prospectively identify patients with non-germline BRCA1 or BRCA2 mutations who may have a homologous recombination deficiency by using a next-generation sequencing assay. An analy-   sis algorithm was developed to predict rucaparib sensitivity by de- tecting tumor BRCA status and whether there is a high genomic loss of heterozygosity representing a DNA “scar” reflecting prior loss of HR repair. Part 1 of ARIEL2 included 204 patients with recurrent, platinum-sensitive, high grade ovarian carcinoma and were classified into three homologous recombination deficiency subgroups based on tumor analysis: BRCA mutant (deleterious germline or somatic); BRCA wild type/loss of heterozygosity   (LOH) high; or BRCA wild type/LOH low. Patients    received
600 mg of rucaparib twice daily. The primary endpoint was PFS, but secondary endpoints also included response rate, response duration, and safety. The risk of progression during treatment   was significantly reduced in the BRCA mutant subgroup (HR,  0.27; 95% CI, 0.16-0.44; P < .0001) and in the BRCA wild    type/LOH high subgroup (HR, 0.62; 95% CI, 0.42-0.90) subgroup compared to the BRCA wild type/LOH low subgroup. More patients in the BRCA mutant subgroup (50.4%; P < .0001 for HR) and in the BRCA wild type/LOH high subgroup (28.0%;   P = .011 for HR) were progression free at 12 months than the BRCA wild type/LOH low subgroup (9.6%). This study suggests that assessment of tumoral LOH can identify patients that have BRCA wild type platinum-sensitive ovarian cancers that may benefit from PARP inhibition with   rucaparib.34

Future Directions and Conclusions

An estimated 11% to 15% of unselected patients with ovarian cancer have germline BRCA1 or BRCA2 mutations.35,36 Given the demonstrated activity of PARP inhibition in germline BRCA1/2- mutated ovarian cancer, Hennessy et al37 sought to investigate whether loss of BRCA function can also occur through somatic mutations, potentially expanding the number of patients who  could benefit from  this treatment.  Two-hundred thirty-five  ovarian  cancer samples were randomly  selected and  analyzed for BRCA mutations. Forty-four BRCA mutations were detected in 43 tumors, including 1 cancer in which both BRCA1 and BRCA2 mutations were detected. Of these tumors, 28    samples had DNA available for analysis. Eleven mutations (9 BRCA1 and   2 BRCA2) were found to be somatic, whereas 17 mutations were found in both tumor and germline DNA. There was no signif-  icant  difference  in  clinical  variables  or  PFS  between  patients with germline BRCA mutations and somatic BRCA mutations. BRCA1/2 deficiency, as defined by the presence of germline or somatic mutations, deletion of BRCA1 or BRCA2, or loss of ex- pression of BRCA1 or BRCA2, was present in 30% of the ovarian tumors analyzed and was associated with significantly prolonged  PFS following surgical cytoreduction when compared with BRCA nonmutants (20.1 and 13.8 months, respectively). The surprising frequency of somatic aberrations found in BRCA1/2 ovarian cancers, with resultant disruption in homologous repair, was postulated to increase the sensitivity of these tumors to PARP inhibition. The authors also suggest that somatic mutations and BRCA1/2 expression loss be routinely assessed in clinical trials investigating the effectiveness of PARP inhibition, in addition to standard  germline  mutation testing.
 
The heterogeneous mechanisms by which tumors can acquire defects in homologous repair has been referred to as “BRCA-   ness”  or  “BRCA-like”  status.38,39  A  gene  expression  profile  for the BRCA-like state has been developed and is associated with response to platinum-based chemotherapy, as well as response    to
PARP inhibition.40 This 60-gene profile was developed after anal- ysis of microarray data from 61 patients with somatic or germline BRCA mutations. Using the gene profile, the authors were able     to predict platinum sensitivity in 8 of 10 patient-derived samples. They also were able to predict sensitivity or resistance to PARP inhibition in 100% (4 of 4) of cell lines. This profile was then    used to categorize 70 patients with sporadic ovarian cancer as BRCA-like (BL) or non–BRCA-like (NBL). Patients with a BL pro- file had improved disease-free survival (34 versus 15 months; log- rank P = .013) and OS (72 versus 41 months; log-rank P = .006) compared with patients with a NBL profile. In a multi- variate analysis,  the  BL  profile  maintained  independent  prognostic value when other clinical variables were controlled. BRCA- like phenotypes  have  also  been  observed  with  hypermethylation  of the BRCA promoter and with alterations of BRCA-associated proteins, including BARD1.41,42 Although further investigation is needed, this BL profile could potentially be used to offer PARP inhibition to a much larger population of patients with ovarian cancer, independent of BRCA mutation  status.

Methods to predict response to PARP inhibition are current-     ly being investigated. Homologous recombination deficiency (HRD) assays are in development, which use next-generation sequencing  to  identify  genome-wide  loss  of  heterozygosity,  seen in patients lacking genes involved in homologous repair, not    just
BRCA1 and BRCA2. These assays have been successful in predict- ing response to rucaparib, another PARP inhibitor.43 The efficacy  of HRD assays in predicting  response  to olaparib  and other  PARP inhibitors is now being investigated (NCT02401347).   The production of Rad51, a known marker of homologous repair, following irradiation of patient-derived xenographs, has been shown to predict response to PARP inhibition ex vivo, with sensitive samples consistently having a low Rad51 foci formation rate.44 CDK12 activity also has been proposed as a marker for resistance to PARP inhibition.45 This kinase promotes homolo- gous repair and confers resistance to PARP inhibitors. FOXO3a expression also is being explored as a potential biomarker in predicting response to inhibition of   PARP.46

Further clinical investigation of olaparib is under way. A planned phase 2 study aims to detect a biomarker signature    that correlates with durable response or SD to cediranib and olaparib in patients with platinum-sensitive ovarian cancer (NCT02345265). Cediranib in combination with olaparib also   is being investigated in the phase 3 setting, following prom-   ising phase 2 results.17 Other phase 1/2 studies are on- going   with olaparib in combination with PI3K pathway inhibitors (NCT01623349),  AKT inhibitors  (NCT02338622), and
mTORC1/2 inhibitors (NCT02208375), Wee1  (NCT02511795), among others. PARP inhibitors also are being investigated in pa- tients with wild-type BRCA-associated disease (NCT02354586). Other PARP inbhitiors are being evaluated in combination with over targeted therapies including niraparib and pembrolizumab (NCT02657889).

Olaparib and PARP inhibition as an anticancer strategy is   an exciting addition to currently available treatment options   for ovarian cancer. More studies are needed to determine    the
optimal settings and combinations in which to administer olapa- rib. A profile of a BRCA-like state may allow expansion of the population able to derive clinical benefit from PARP inhibition, and should be investigated in future   trials.

Acknowledgments:

Dr Previs is supported by NIH T32 training grant CA101642.     Dr Coleman is supported in part by CPRIT RP120214, Ovarian Cancer Research Fund Program Project Development Grant, the Judy Reis, Albert L. Pisani MD Ovarian Cancer Research Fund, and the Ann Rife Cox Chair in   Gynecology.
 
Author affiliations: Drs Previs and Coleman are from the De- partment of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Hous-   ton. Dr Dalton is from the Department of Arizona Oncology, Phoenix.
Author disclosures: Drs Previs and Dalton report no relevant financial conflicts of interest to disclose. Dr Coleman has served  as an uncompensated advisor for AstraZeneca; he also has re-  ceived nonfinancial support and a grant from Merck, and has re- ceived clinical trial grants from the following companies: Janssen Pharmaceuticals, Clovis Oncology, Amgen, Novartis, Merrimack Pharmaceuticals,  Millennium  Pharmaceuticals,  OncoMed, Array BioPharma,  and  EMD Serono.
Address correspondence to: Robert L. Coleman, MD, Depart- ment of Gynecologic Oncology and Cancer Biology, Unit 1362, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030. Phone: (713)   745-3357;
fax:  (713)  792-7586;  email: rcoleman@mdanderson.org.

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