Ovarian cancer is the most lethal gynecologic cancer and the fifth leading cause of cancer death among women in the United States.1 No effective screening tests are available, and more than 70% of patients are diagnosed with advanced-stage disease.2 Despite a high initial response rate to platinum/taxane-based therapy in patients with advanced ovarian cancer, the effectiveness of treatment diminishes over time, and most patients relapse.2-5 Although platinum retreatment is used in patients thought to be sensitive to platinum, this therapy has diminishing responsiveness and shorter progression-free survival (PFS).2 Treatment for recurrent disease depends on several factors, including duration of initial treatment response, occurrence of antecedent or persistent adverse events (AEs), performance status, histology, location and burden of disease, and tumor genomics such as BRCA mutation status.3 For patients with platinum-sensitive recurrent ovarian carcinoma who have achieved a response to a platinum doublet, maintenance therapy with targeted agents has resulted in greater prolongation of PFS compared with observation/placebo.3-10 However, clinical benefit is typically transient, which represents a significant unmet need in the treatment of ovarian cancer, prompting a search for new therapies and tools to identify patients who may benefit most from these therapies, as well as to identify the optimal therapeutic strategy.
There is genuine excitement within the gynecologic cancer clinical and research communities regarding the potential role of poly (ADP-ribose) polymerase (PARP) inhibitors in the management of patients with ovarian cancer. Paclitaxel was introduced as a treatment for ovarian cancer more than 20 years ago. However, in the past 5 to 6 years, there has been a substantial increase in phase 3 clinical trial data challenging the heretofore existing treatment paradigms and changing current thinking about the disease and its treatment.
The 17-member PARP superfamily of nuclear enzymes includes PARP1, PARP2, and PARP3, which are activated by DNA damage and are key mediators in the repair of single-strand breaks.11 Inhibition of PARP1, PARP2, and PARP3 results in collapsed DNA replication forks and development of double-strand breaks, which require repair through the BRCA1- and BRCA2-mediated homologous recombination repair pathway.11,12-14 Defects in the homologous recombination repair pathway—for example, a deleterious BRCA1 or BRCA2 (BRCA1/2) mutation—cause homologous recombination deficiency (HRD) and can selectively sensitize tumors to PARP inhibition through synthetic lethality.11,15 It is estimated that up to 50% of high-grade serous ovarian carcinomas may exhibit HRD, with approximately 22% to 24% harboring a germline BRCA1/2 mutation and 6% to 9% a somatic BRCA1/2 mutation.16,17 High genomic loss of heterozygosity (LOH) is a potential marker of HRD, including in cancers without a BRCA mutation, and thus, sensitivity to PARP inhibitor activity.3,18-21
Rucaparib in Ovarian Cancer
Rucaparib (Rubraca®), an oral, small molecule inhibitor of PARP1, PARP2, and PARP3, has been approved by the US Food and Drug Administration (FDA) for (1) the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete response (CR) or partial response (PR) to platinum-based chemotherapy, and (2) the treatment of adult patients with deleterious BRCA mutation (germline and/or somatic)-associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with 2 or more chemotherapies.22 Approval of rucaparib for maintenance therapy of patients with recurrent ovarian carcinoma after response to platinum therapy was based primarily on data from ARIEL3, a multicentered, randomized, double-blind, placebo-controlled phase 3 clinical trial.3
Highlights from the Phase 3 ARIEL3 Clinical Trial
ARIEL3 (NCT01968213) was a multicenter, randomized, double-blind, placebo-controlled phase 3 study assessing efficacy and safety of rucaparib as maintenance treatment following response to second-line or later platinum-based chemotherapy for platinum-sensitive relapse of high-grade serous or endometrioid epithelial ovarian, primary peritoneal, or fallopian tube cancer.3 Patients must have achieved a radiologic CR per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST1.1) or a PR per RECIST1.1 or a serologic response per Gynecologic Cancer InterGroup (GCIG) cancer antigen 125 (CA-125) criteria, when disease was not measurable per RECIST1.1, following the last platinum-based chemotherapy, with all the patients required per trial eligibility to have CA-125 below the upper limit of normal (ULN). Patients achieving PR after platinum-based chemotherapy and with measurable residual disease were still suitable for enrollment. Patients were considered ineligible if they had symptomatic or untreated central nervous system metastases, had received anticancer therapy within 14 days of starting the study, or had received previous treatment with a PARP inhibitor.
A total of 564 patients were enrolled and randomized 2:1 to receive rucaparib 600 mg twice daily (n = 375) or placebo (n = 189) in continuous 28-day cycles, stratified based on HRD as assessed by gene mutation status of archival tumor tissue samples, as follows:
- Mutation in BRCA1 or BRCA2 (BRCA mutant)
- Mutation in a non-BRCA gene associated with homologous recombination from a 28-gene panel
- No mutation in BRCA or a homologous recombination panel gene.
Patients were also stratified by radiologic previous progression-free interval following the penultimate platinum-based chemotherapy (6 to ≤12 months or >12 months), as well as best response to last platinum-based chemotherapy (CR per RECIST1.1 or PR per RECIST1.1 or serologic response per GCIG CA-125 criteria). Randomization had to occur within 8 weeks from the last dose of platinum-based chemotherapy.3 The study design of ARIEL3 is shown in Figure 1.3,23
The primary objective of the trial was to assess investigator-assessed PFS in 3 different nested predefined HRD subgroups: (1) BRCA mutant (germline or somatic); (2) HRD (BRCA mutant or BRCA wild-type and high LOH) assessed using the Foundation Medicine T5 next-generation sequencing (NGS) assay and a 16% cutoff as identified retrospectively from the results of the ARIEL2 Part I study, a multicenter, open-label, phase 2 trial24; and (3) the intention-to-treat (ITT) population.3 Secondary objectives included PFS as assessed by blinded, independent central review, overall survival, safety, patient-reported outcomes, and overall response rate as an exploratory objective in patients with measurable disease at study entry.3 In addition, ARIEL3 was designed to prospectively test genomic LOH as a potential signature of HRD and a potential predictive biomarker of response to rucaparib, based on the optimized results of the ARIEL2 study.24,25
As shown in Figure 2, rucaparib significantly improved investigator-assessed median PFS in all 3 groups: (1) those with deleterious BRCA mutation (Panels A-C): 16.6 months in the rucaparib group (n = 130) versus 5.4 months in the placebo group (n = 66) (HR, 0.23; 95% confidence interval [CI], 0.16-0.34; P <.0001); (2) those with HRD (Panel B): 13.6 months in the rucaparib group (n = 236) versus 5.4 months in the placebo group (n = 118) (HR, 0.32; 95% CI, 0.24-0.42; P <.0001); and (3) in the ITT population (Panel C): 10.8 months in the rucaparib group versus 5.4 months in the placebo group (HR, 0.36; 95% CI, 0.30-0.45; P <.0001). These significant improvements in PFS in the rucaparib groups were observed regardless of whether PFS was assessed by the investigators (Panels A-C) or through a blinded independent central review (BICR; Panels D-F) (Figure 2).3
As shown in Figure 3, a preplanned subgroup analysis confirmed the statistically significant improvement in PFS with rucaparib versus placebo in all the subgroups, including (1) BRCA mutation types (BRCA1 vs BRCA2; germline vs somatic); (2) measurable disease at baseline (present vs absent); (3) bulky residual disease (defined as any tumor >2 cm) at baseline (present vs absent); (4) number of previous lines of chemotherapy (2 vs ≥3); (5) previous use of bevacizumab (yes vs no); (6) number of previous platinum regimens (2 vs ≥3); (7) time to progression with penultimate platinum-based chemotherapy (6 to <12 months vs ≥12 months); and (8) response to last platinum-based chemotherapy (CR per RECIST1.1 vs PR per RECIST1.1 or GCIG CA-125 response criteria). Response rate according to RECIST1.1 criteria was assessed in patients with measurable disease at the time of enrollment (n = 207 in the ITT population); 18% (26/141) of patients in the rucaparib arm achieved a confirmed objective response (7% CR, 10/141) and 8% (5/66) in the placebo group (2% CR, 1/66).3
Moreover, further supporting the efficacy observed in the ITT population, in the non-nested subgroups of patients with BRCA wild-type carcinoma, an investigator-assessed PFS benefit was observed with rucaparib versus placebo in patients with high LOH carcinomas (median 9.7 months vs 5.4 months, respectively [HR, 0.44; 95% CI, 0.29-0.66; P <.0001]) and low LOH carcinomas (6.7 months vs 5.4 months, respectively [HR, 0.58; 95% CI, 0.40-0.85; P <.0049]) (Figure 4).3
A safety analysis was conducted in 372 patients receiving rucaparib and 189 receiving placebo. Treatment-emergent AEs (TEAEs) were observed in 100% of patients in the rucaparib group and 96% in the placebo group (Table 1).3 The majority of TEAEs were manageable, and the most common were consistent with those reported in previous studies,24,25 including nausea, asthenia/fatigue, dysgeusia, anemia, constipation, and vomiting.3 Grade ≥3 TEAEs occurred in 56% of patients in the rucaparib arm and 15% in the placebo arm, with the most common being anemia and increased transaminases, which were generally transient, self-limiting, and not associated with abnormal increases in bilirubin or other criteria for drug-induced hepatotoxicity. Anemia was managed with supportive care and rucaparib treatment interruption and/or dose reductions3; 76 patients (20.4%) in the rucaparib group had ≥1 blood transfusions.26 The most common serious TEAEs occurred in 21% of patients receiving rucaparib and in 11% of patients receiving placebo.3
Treatment interruption attributed to a TEAE occurred in 237 patients (64%) in the rucaparib group and 19 patients (10%) in the placebo group, and dose reduction attributed to a TEAE occurred in 203 patients (55%) in the rucaparib group and 8 patients (4%) in the placebo group.3 Both a treatment interruption and a dose reduction attributed to a TEAE occurred in 117 patients (31%) in the rucaparib group and 6 patients (3%) in the placebo group. Of patients who received rucaparib, 50 (13%) discontinued because of a TEAE (excluding disease progression) versus 3 (2%) in the placebo group.3
Dose modification principles for ARIEL3 included withholding or reducing the study drug if any of the following AEs were observed: grade 3/4 hematologic toxicity, grade 3/4 nonhematologic toxicity (exceptions: alopecia, or nausea, vomiting, or diarrhea adequately controlled with systemic antiemetic/antidiarrheal medications), or intolerable grade 2 toxicities.3,26 Based on the results of ARIEL3, the dose modification schedule for rucaparib has been established as shown in Table 2.22,23,26
The management of rucaparib-associated TEAEs has been studied in a number of centers. In general, the recommendations suggest adhering to National Comprehensive Cancer Network guidelines, including the following23,26:
- • For grade 3/4 anemia:
- o Hold PARP inhibitor, administer blood transfusion if necessary, repeat laboratory tests, restart PARP inhibitor at the same or reduced dose
- • For grade 4 elevated liver function tests:
- o Hold PARP inhibitor, avoid hepatotoxic medications, instruct patient to avoid alcohol, repeat laboratory tests, restart PARP inhibitor at the same or reduced dose
- • For grade 4 elevated creatinine:
- o Hold PARP inhibitor, administer intravenous fluids, avoid nephrotoxic medications, repeat laboratory tests, restart PARP inhibitor at the same or reduced dose.
The ARIEL3 study demonstrated the role of rucaparib as effective maintenance treatment following response to platinum-based chemotherapy in patients with platinum-sensitive relapse of ovarian carcinoma.3 Rucaparib was shown to be active not only in patients with tumors with deleterious BRCA mutations but also in patients with tumors with non–BRCA-related HRD; however, the overall population enrolled in the trial, including patients with tumors that were BRCA wild-type and low LOH, achieved a benefit from rucaparib. Although the Foundation Medicine T5 NGS LOH score could be used to select patients who would benefit the most from rucaparib, it was not completely predictive as a biomarker of response, given the fact that significant improvement in PFS was also observed in patients with tumors that were BRCA wild-type and low LOH.3
Differentiating Rucaparib from Other PARP Inhibitors as Maintenance Therapy for Advanced Ovarian Cancer
The impressive clinical trial data discussed in this article is testimony to the utility of PARP inhibitors and the realistic potential of these agents to favorably affect the natural history of ovarian cancer in a substantial proportion of individuals. Phase 3 data are now available from randomized, double-blind, placebo-controlled clinical trials with the 3 PARP inhibitors that are currently FDA approved; however, important differences should be noted in their eligibility criteria, treatment and control arms, and clinical end points.
The results of ARIEL3 are consistent with those of the other placebo-controlled studies of PARP inhibitors in the maintenance treatment setting (ENGOT-OV16/NOVA studying niraparib4 and Study 197,27 and SOLO2/ENGOT-Ov2110 studying olaparib); however, direct comparisons cannot be made because of differences in the patient groups analyzed. For example, SOLO2/ENGOT-Ov21 enrolled only patients with a germline BRCA mutation10; the definition of HRD in this study included patients with germline mutations in BRCA and those with non–BRCA-related HRD4; HRD-positive status was determined by the myChoice® HRD test. Any tumor that scored ≥42 or had a deleterious or suspected deleterious BRCA1/2 mutation was considered HRD-positive via this test. Within the non-germline BRCA-mutant cohort, tumors with somatic BRCA mutations were identified by this test. These tumors have a defective homologous recombination repair pathway. There were also differences in the method of primary end point assessment (eg, investigator vs BICR) across studies3,4,7,10,27; and study design varied such that residual disease was restricted to <2 cm in ENGOT-OV16/NOVA,4,28 which was not the case in ARIEL3.3
Moreover, although having a CA-125 concentration of <ULN is not a requirement of response (according to GCIG CA-125 criteria or a RECIST1.1 PR), ARIEL3 included this requirement to ensure that patients had controlled disease at study entry,3 whereas it is unclear how many patients in the olaparib and niraparib trials had CA-125 concentrations >ULN at study entry.4,7,10 This difference may be important; however, whether inclusion of patients with CA-125 concentrations >ULN affects the efficacy of PARP inhibitors in the maintenance treatment setting is currently unknown.3
There are additional important differences between ARIEL3 and studies with other PARP inhibitors in the maintenance treatment of ovarian carcinoma. For example, a unique feature of ARIEL3 was that patients with carcinomas associated with either a germline or a somatic BRCA mutation were both included in the 3 nested cohorts.3 Furthermore, enrollment of patients on the basis of target lesion size in patients with residual disease (ie, those who had achieved a PR to previous platinum therapy) was not restricted in ARIEL3. In that regard, a number of patients with measurable residual disease at study entry showed further reduction in tumor burden with rucaparib maintenance treatment, including conversion to CR.3
Rucaparib is a potent inhibitor of PARP1, PARP2, and PARP3. The ARIEL3 study has established the role of rucaparib as maintenance treatment following response to platinum-based chemotherapy for platinum-sensitive relapse of high-grade ovarian cancer. PFS was significantly better in patients treated with rucaparib in the 3 different cohorts: deleterious BRCA1/2 mutation, HRD, and ITT population. The Foundation Medicine T5 NGS assay was confirmed to be a useful tool in selecting patients who would benefit most from rucaparib; however, it was not completely predictive as a biomarker, since benefit from rucaparib was also observed in patients with tumors that were BRCA wild-type and low LOH.
ARIEL3 was the first phase 3 trial to prospectively assess the primary end point of PFS in patients with recurrent ovarian carcinoma associated with HRD.3 A preplanned analysis of PFS in patients with a BRCA wild-type and high LOH carcinoma showed that patients receiving rucaparib had an increase in median PFS compared with placebo, demonstrating that the improvement observed in the HRD cohort was not driven solely by patients with a BRCA-mutant carcinoma. The results from ARIEL3 led to FDA approval of rucaparib for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a CR or PR to platinum-based chemotherapy.
Although different PARP inhibitors have been shown to be effective in this setting, a direct comparative analysis of agents is not feasible, primarily because the trials assessing their activity differ significantly from one another in the selection of patients (only BRCA1/2 mutated or also BRCA1/2 wild-type), HRD definition, study design, and inclusion or exclusion of patients with residual bulky disease, or abnormal CA-125 levels. Moreover, each PARP inhibitor has a unique toxicity profile.
Further research is warranted to define biomarkers that may be able to predict PARP inhibitor activity and overcome mechanisms of resistance to PARP inhibitors, as well as to investigate the most appropriate combination of PARP inhibitors with other agents such as immune checkpoint inhibitors, antivascular agents, cell-cycle inhibitors, or other DNA-damaging agents such as chemotherapy and radiotherapy.
- Centers for Disease Control and Prevention (CDC). Gynecologic cancers: ovarian cancer statistics. CDC website. www.cdc.gov/cancer/ovarian/statistics/index.htm. Updated June 7, 2017. Accessed April 11, 2018.
- Hanker LC, Loibl S, Burchardi N, et al; on behalf of the AGO and GINECO Study Group. The impact of second to sixth line therapy on survival of relapsed ovarian cancer after primary taxane/platinum-based therapy. Ann Oncol. 2012;23:2605-2612.
- Coleman RL, Oza AM, Lorusso D, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390:1949-1961.
- Mirza MR, Monk BJ, Herrstedt J, et al; for the ENGOT-OV16/NOVA Investigators. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375:2154-2164.
- McMeekin DS, Tillmanns T, Chaudry T, et al. Timing isn’t everything: an analysis of when to start salvage chemotherapy in ovarian cancer. Gynecol Oncol. 2004;95:157-164.
- Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012;30:2039-2045.
- Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366:1382-1392.
- Coleman RL, Brady MF, Herzog TJ, et al. Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18:779-791.
- Ledermann JA, Embleton AC, Raja F, et al; on behalf of the ICON6 Collaborators. Cediranib in patients with relapsed platinum-sensitive ovarian cancer (ICON6): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016;387:1066-1074.
- Pujade-Lauraine E, Ledermann JA, Selle F, et al; SOLO2/ENGOT-Ov21 Investigators. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18:1274-1284.
- Scott CL, Swisher EM, Kaufmann SH. Poly (ADP-ribose) polymerase inhibitors: recent advances and future development. J Clin Oncol. 2015;33:1397-1406.
- Venkitaraman AR. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 2002;108:171-182.
- Moynahan ME, Pierce AJ, Jasin M. BRCA2 is required for homology-directed repair of chromosomal breaks. Mol Cell. 2001;7:263-272.
- Moynahan ME, Chiu JW, Koller BH, Jasin M. Brca1 controls homology-directed DNA repair. Mol Cell. 1999;4:511-518.
- Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361:123-134.
- Pennington KP, Walsh T, Harrell MI, et al. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res. 2014;20:764-775.
- Konstantinopoulos PA, Ceccaldi R, Shapiro GI, D’Andrea AD. Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer. Cancer Discov. 2015;5:1137-1154.
- Watkins JA, Irshad S, Grigoriadis A, Tutt AN. Genomic scars as biomarkers of homologous recombination deficiency and drug response in breast and ovarian cancers. Breast Cancer Res. 2014;16:211.
- Abkevich V, Timms KM, Hennessy BT, et al. Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. Br J Cancer. 2012;107:1776-1782.
- Pedersen B, Konstantinopoulos PA, Spillman MA, De S. Copy neutral loss of heterozygosity is more frequent in older ovarian cancer patients. Genes Chromosomes Cancer. 2013;52:794-801.
- Marquard AM, Eklund AC, Joshi T, et al. Pan-cancer analysis of genomic scar signatures associated with homologous recombination deficiency suggests novel indications for existing cancer drugs. Biomark Res. 2015;3:9.
- Rubraca® (rucaparib) [prescribing information]. Boulder, CO: Clovis Oncology, Inc; 2018.
- Khan A, O’Malley DM. ARIEL3: a phase 3, randomized, double-blind study of rucaparib vs placebo following response to platinum-based chemotherapy for recurrent ovarian carcinoma. Presented at: 14th Annual Conference of the Hematology/Oncology Pharmacy Association; March 21-24, 2018; Denver, CO. Poster CT11.
- Swisher EM, Lin KK, Oza AM, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part I): an international, multicentre, open-label phase 2 trial. Lancet Oncol. 2017;18:75-87.
- Oza AM, Tinker AV, Oaknin A, et al. Antitumor activity and safety of the PARP inhibitor rucaparib in patients with high-grade ovarian carcinoma and a germline or somatic BRCA1 or BRCA2 mutation: integrated analysis of data from Study 10 and ARIEL2. Gynecol Oncol. 2017;147:267-275.
- Soldan K. ARIEL3: a phase 3, randomized, double-blind study of rucaparib vs placebo following response to platinum-based chemotherapy for recurrent ovarian carcinoma. Presented at: 35th Annual Symposium of the Society of Gynecologic Nurse Oncologists; March 21-24, 2018; Albuquerque, NM.
- Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 2014;15:852-861.
- Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer [appendix]. N Engl J Med. 2016;375:2154-2164. www.nejm.org/doi/suppl/10.1056/NEJMoa1611310/suppl_file/nejmoa1611310_appendix.pdf. Accessed May 16, 2018.