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.
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.
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
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.
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.
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.
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).
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.
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.
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
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.
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.
fax: (713) 792-7586; email: firstname.lastname@example.org.
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