Sandra Goble

Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial

BACKGROUND Poly(ADP-ribose) polymerase (PARP) inhibitors have activity in ovarian carcinomas with homologous recombination deficiency. Along with BRCA1 and BRCA2 (BRCA) mutations genomic loss of heterozygosity (LOH) might also represent homologous recombination deficiency. In ARIEL2, we assessed the ability of tumour genomic LOH, quantified with a next-generation sequencing assay, to predict response to rucaparib, an oral PARP inhibitor. METHODS ARIEL2 is an international, multicentre, two-part, phase 2, open-label study done at 49 hospitals and cancer centres in Australia, Canada, France, Spain, the UK, and the USA. In ARIEL2 Part 1, patients with recurrent, platinum-sensitive, high-grade ovarian carcinoma were classified into one of three predefined homologous recombination deficiency subgroups on the basis of tumour mutational analysis: BRCA mutant (deleterious germline or somatic), BRCA wild-type and LOH high (LOH high group), or BRCA wild-type and LOH low (LOH low group). We prespecified a cutoff of 14% or more genomic LOH for LOH high. Patients began treatment with oral rucaparib at 600 mg twice per day for continuous 28 day cycles until disease progression or any other reason for discontinuation. The primary endpoint was progression-free survival. All patients treated with at least one dose of rucaparib were included in the safety analyses and all treated patients who were classified were included in the primary endpoint analysis. This trial is registered with ClinicalTrials.gov, number NCT01891344. Enrolment into ARIEL2 Part 1 is complete, although an extension (Part 2) is ongoing. FINDINGS 256 patients were screened and 206 were enrolled between Oct 30, 2013, and Dec 19, 2014. At the data cutoff date (Jan 18, 2016), 204 patients had received rucaparib, with 28 patients remaining in the study. 192 patients could be classified into one of the three predefined homologous recombination deficiency subgroups: BRCA mutant (n=40), LOH high (n=82), or LOH low (n=70). Tumours from 12 patients were established as BRCA wild-type, but could not be classified for LOH, because of insufficient neoplastic nuclei in the sample. The median duration of treatment for the 204 patients was 5·7 months (IQR 2·8-10·1). 24 patients in the BRCA mutant subgroup, 56 patients in the LOH high subgroup, and 59 patients in the LOH low subgroup had disease progression or died. Median progression-free survival after rucaparib treatment was 12·8 months (95% CI 9·0-14·7) in the BRCA mutant subgroup, 5·7 months (5·3-7·6) in the LOH high subgroup, and 5·2 months (3·6-5·5) in the LOH low subgroup. Progression-free survival was significantly longer in the BRCA mutant (hazard ratio 0·27, 95% CI 0·16-0·44, p<0·0001) and LOH high (0·62, 0·42-0·90, p=0·011) subgroups compared with the LOH low subgroup. The most common grade 3 or worse treatment-emergent adverse events were anaemia or decreased haemoglobin (45 [22%] patients), and elevations in alanine aminotransferase or aspartate aminotransferase (25 [12%]). Common serious adverse events included small intestinal obstruction (10 [5%] of 204 patients), malignant neoplasm progression (10 [5%]), and anaemia (nine [4%]). Three patients died during the study (two because of disease progression and one because of sepsis and disease progression). No treatment-related deaths occurred. INTERPRETATION In patients with BRCA mutant or BRCA wild-type and LOH high platinum-sensitive ovarian carcinomas treated with rucaparib, progression-free survival was longer than in patients with BRCA wild-type LOH low carcinomas. Our results suggest that assessment of tumour LOH can be used to identify patients with BRCA wild-type platinum-sensitive ovarian cancers who might benefit from rucaparib. These results extend the potential usefulness of PARP inhibitors in the treatment setting beyond BRCA mutant tumours. FUNDING Clovis Oncology, US Department of Defense Ovarian Cancer Research Program, Stand Up To Cancer-Ovarian Cancer Research Fund Alliance-National Ovarian Cancer Coalition Dream Team Translational Research Grant, and V Foundation Translational Award.

A Phase I-II Study of the Oral PARP Inhibitor Rucaparib in Patients with Germline BRCA1/2-Mutated Ovarian Carcinoma or Other Solid Tumors

Purpose: Rucaparib is a potent, oral, small-molecule PARP inhibitor. This phase I–II study was the first to evaluate single-agent oral rucaparib at multiple doses. Experimental Design: Part 1 (phase I) sought to determine the MTD, recommended phase II dose (RP2D), and pharmacokinetics of oral rucaparib administered in 21-day continuous cycles in patients with advanced solid tumors. Part 2A (phase II) enrolled patients with platinum-sensitive, high-grade ovarian carcinoma (HGOC) associated with a germline BRCA1/2 mutation who received two to four prior regimens and had a progression-free interval of 6 months or more following their most recent platinum therapy. The primary endpoint was investigator-assessed objective response rate (ORR) by RECIST version 1.1. Results: In part 1, 56 patients received oral rucaparib (40 to 500 mg once daily and 240 to 840 mg twice daily). No MTD was identified per protocol-defined criteria; 600 mg twice daily was selected as the RP2D based on manageable toxicity and clinical activity. Pharmacokinetics were approximately dose-proportional across all dose levels. In part 2A, 42 patients with germline BRCA1/2–mutated HGOC received rucaparib 600 mg twice daily. Investigator-assessed ORR was 59.5%. The most common treatment-emergent adverse events (all grades) were asthenia/fatigue (85.7%; 36/42), nausea (83.3%; 35/42), anemia (71.4%; 30/42), alanine transaminase and/or aspartate transaminase elevations (57.1%; 24/42), and vomiting (54.8%; 23/42). Among 98 patients, 5 (5.1%) discontinued because of an adverse event (excluding disease progression). Conclusions: Rucaparib was tolerable and had activity in patients with platinum-sensitive germline BRCA1/2–mutated HGOC. Clin Cancer Res; 23(15); 4095–106. ©2017 AACR.

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

OBJECTIVE An integrated analysis was undertaken to characterize the antitumor activity and safety profile of the oral poly(ADP-ribose) polymerase inhibitor rucaparib in patients with relapsed high-grade ovarian carcinoma (HGOC). METHODS Eligible patients from Study 10 (NCT01482715) and ARIEL2 (NCT01891344) who received a starting dose of oral rucaparib 600mg twice daily (BID) with or without food were included in these analyses. The integrated efficacy population included patients with HGOC and a deleterious germline or somatic BRCA1 or BRCA2 (BRCA1/2) mutation who received at least two prior chemotherapies and were sensitive, resistant, or refractory to platinum-based chemotherapy. The primary endpoint was investigator-assessed confirmed objective response rate (ORR). Secondary endpoints included duration of response (DOR) and progression-free survival (PFS). The integrated safety population included patients with HGOC who received at least one dose of rucaparib 600mg BID, irrespective of BRCA1/2 mutation status and prior treatments. RESULTS In the efficacy population (n=106), ORR was 53.8% (95% confidence interval [CI], 43.8-63.5); 8.5% and 45.3% of patients achieved complete and partial responses, respectively. Median DOR was 9.2months (95% CI, 6.6-11.6). In the safety population (n=377), the most frequent treatment-emergent adverse events (AEs) were nausea, asthenia/fatigue, vomiting, and anemia/hemoglobin decreased. The most common grade ≥3 treatment-emergent AE was anemia/hemoglobin decreased. Treatment-emergent AEs led to treatment interruption, dose reduction, and treatment discontinuation in 58.6%, 45.9%, and 9.8% of patients, respectively. No treatment-related deaths occurred. CONCLUSIONS Rucaparib has antitumor activity in advanced BRCA1/2-mutated HGOC and a manageable safety profile.

2746 A Phase 2 open-label, multicenter study of single-agent rucaparib in the treatment of patients with relapsed ovarian cancer and a deleterious BRCA mutation

5513 Background: Rucaparib is a potent oral PARP inhibitor that has shown robust activity in patients (pts) with homologous recombination deficient (HRD) tumors, with the highest response rates observed in ovarian and breast cancer pts harboring deleterious germline BRCA mutations (gBRCAmut). This phase II study (NCT 01891344) evaluated the efficacy and safety of rucaparib in pts with relapsed gBRCAmut high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer (EOC/FTC/PPC). Methods: Women with gBRCAmut EOC/FTC/PPC who received 2-4 prior chemotherapy (chemo) regimens and had a progression-free interval (PFI) ≥ 6 months after their last platinum dose were enrolled. ECOG PS 0-1 and adequate organ function were required. Pts received oral rucaparib 600 mg BID in 21 day cycles until disease progression. The primary endpoint was objective response rate (ORR) by RECIST 1.1. Results: 35 pts have been enrolled. Median age was 55 years (range 44-84). The median number of prior chemo regimens was 2...

A phase I study of intravenous and oral rucaparib in combination with chemotherapy in patients with advanced solid tumours

Background:This study evaluated safety, pharmacokinetics, and clinical activity of intravenous and oral rucaparib, a poly(ADP-ribose) polymerase inhibitor, combined with chemotherapy in patients with advanced solid tumours.Methods:Initially, patients received escalating doses of intravenous rucaparib combined with carboplatin, carboplatin/paclitaxel, cisplatin/pemetrexed, or epirubicin/cyclophosphamide. Subsequently, the study was amended to focus on oral rucaparib (once daily, days 1–14) combined with carboplatin (day 1) in 21-day cycles. Dose-limiting toxicities (DLTs) were assessed in cycle 1 and safety in all cycles.Results:Eighty-five patients were enrolled (22 breast, 15 ovarian/peritoneal, and 48 other primary cancers), with a median of three prior therapies (range, 1–7). Neutropenia (27.1%) and thrombocytopenia (18.8%) were the most common grade ⩾3 toxicities across combinations and were DLTs with the oral rucaparib/carboplatin combination. Maximum tolerated dose for the combination was 240 mg per day oral rucaparib and carboplatin area under the curve 5 mg ml−1 min−1. Oral rucaparib demonstrated dose-proportional kinetics, a long half-life (≈17 h), and good bioavailability (36%). Pharmacokinetics were unchanged by carboplatin coadministration. The rucaparib/carboplatin combination had radiologic antitumour activity, primarily in BRCA1- or BRCA2-mutated breast and ovarian/peritoneal cancers.Conclusions:Oral rucaparib can be safely combined with a clinically relevant dose of carboplatin in patients with advanced solid tumours (Trial registration ID: NCT01009190).

Rucaparib Monotherapy in Patients With Pancreatic Cancer and a Known Deleterious BRCA Mutation

Purpose Pancreatic cancer has a poor prognosis and limited treatment options. Approximately 9% of pancreatic cancers harbor a germline or somatic BRCA1 or BRCA2 (BRCA1/2) mutation. Because poly (ADP-ribose) polymerase inhibitors have significant activity in BRCA1/2-mutant ovarian and breast cancers, RUCAPANC investigated the efficacy and safety of rucaparib in BRCA1/2-mutant pancreatic cancer. Patients and Methods RUCAPANC enrolled patients with measurable locally advanced/metastatic pancreatic cancer who had received one to two prior chemotherapy regimens. Patients received oral rucaparib (600 mg twice daily) until disease progression. The primary end point was objective response rate. Results Nineteen patients were enrolled. Sixteen of 19 BRCA1/2 mutations were germ-line; three were somatic. Patients had received a median of two prior chemotherapy regimens. Four patients achieved a response; two partial responses and one complete response (CR) were confirmed (objective response rate, 15.8%; 3 of 19), with an additional CR unconfirmed. The disease control rate (CR, partial response, or stable disease for ≥ 12 weeks) was 31.6% (6 of 19) in all patients and 44.4% (4 of 9) in those who had received one prior chemotherapy regimen. As prespecified in the protocol, enrollment was stopped because of an insufficient response rate among the first 15 patients. Treatment-emergent adverse events included nausea (63.2%) and anemia (47.4%). Grade ≥ 3 adverse events included anemia (31.6%), fatigue (15.8%), and ascites (15.8%). Secondary resistance mutations were detected in circulating free tumor DNA in two patients with a germline BRCA2 mutation. These mutations are predicted to lead to the reversion of a somatic-not germline-mutation. Conclusion Rucaparib provided clinical benefit to patients with advanced pancreatic cancer and a BRCA1/2 mutation, and demonstrated an acceptable safety profile. Additional trials of rucaparib in this population are warranted.

Pharmacokinetic Study of Rucaparib in Patients With Advanced Solid Tumors

The phase 1‐2 study CO‐338‐010 (Study 10; NCT01482715) is evaluating single‐agent rucaparib, a poly(ADP‐ribose) polymerase inhibitor, administered orally to patients with an advanced solid tumor. In the dose escalation phase (Part 1), we characterized the single‐dose and steady‐state pharmacokinetic profiles of rucaparib administered once daily (QD; dose range, 40‐500 mg; n = 16) or twice daily (BID; dose range, 240‐840 mg; n = 30). Across all dosing schedules examined, the plasma exposure of rucaparib was approximately dose proportional; half‐life was approximately 17 hours, and median time to maximum concentration (tmax) ranged from 1.5 to 6.0 hours after a single dose and 1.5 to 4.0 hours following repeated dosing. The steady‐state accumulation ratio ranged from 1.60 to 2.33 following QD dosing and 1.47 to 5.44 following BID dosing. No effect of food on rucaparib pharmacokinetics was observed with a single dose of 40 mg (n = 3) or 300 mg (n = 6). In a phase 2 portion of the study (Part 3), the pharmacokinetic profile of rucaparib was further evaluated at the recommended phase 2 dose of 600 mg BID (n = 26). The mean (coefficient of variation) steady‐state maximum concentration (Cmax) and area under the concentration‐time curve from time zero to 12 hours (AUC0‐12h) were 1940 ng/mL (54%) and 16 900 ng ⋅ h/mL (54%), respectively. A high‐fat meal moderately increased rucaparib exposure. The fed‐to‐fasted geometric mean ratios (90% confidence interval [CI]) for AUC0‐24h and Cmax were 138% (117%‐162%) and 120% (99.1%‐146%); the median (90%CI) tmax delay was 2.5 (0.5‐4.4) hours.

Abstract AP28:BRCA1andRAD51CPromoter Hypermethylation Confer Sensitivity to PARP Inhibitors in Patients with Platinum Sensitive Ovarian Carcinoma

Germline and somatic mutations in BRCA1 and BRCA2 (BRCA) confer PARP inhibitor sensitivity. Promoter hypermethylation is an alternate mechanism of gene down-regulation, and BRCA1 promoter methylation is relatively common in sporadic ovarian cancer. The clinical significance of BRCA1 methylation is less clear than for mutations, as the Cancer Genome Atlas (TCGA) and others have failed to show improved survival in ovarian carcinomas with BRCA1 methylation. No one has previously tested whether BRCA1 methylation confers in vivo sensitivity to PARP inhibitors in patients with ovarian cancer. ARIEL2 is a phase 2 study of the PARP inhibitor rucaparib in patients with recurrent platinum sensitive high-grade ovarian, peritoneal or fallopian tube carcinoma. At enrollment, ARIEL2 required pre-treatment tumor biopsies with the goal of developing tissue predictors of PARP inhibitor sensitivity other than BRCA mutations. The number of women with known germline mutations was capped at 15 patients in order to predominantly enroll BRCA wildtype cases. As presented at ASCO 2016, in cases with no BRCA mutations, a high fraction of genomic loss of heterozygosity (LOH) significantly predicted a better progression-free survival (the primary endpoint), longer duration of response, and a higher fraction of responders compared to cases with low LOH. We assessed BRCA1 and RAD51C promoter hypermethylation using methylation-sensitive polymerase chain reaction in paired archival and pre-treatment biopsies from patients on ARIEL2. Of 165 cases for which methylation analyses were completed, 21 (12.7%) were methylated at the BRCA1 promoter and four (2.4%) at the RAD51C promoter. Methylation of BRCA1 and RAD51C was mutually exclusive with mutation in BRCA or other homologous recombination genes. All four cases with RAD51C methylation and 15/19 (78.9%) with BRCA1 methylation were associated with high LOH. In 90 paired samples archival and pre-treatment tissues, RAD51C methylation was 100% concordant and BRCA1 methylation was highly concordant (p Citation Format: Elizabeth Swisher, Maria Harrell, Kevin K. Lin, Clare Scott, Sandra Goble, Amit Oza, Robert L. Coleman, Gottfried Konecny, Anna V. Tinker, David M. O9Malley, Rebecca Kristeleit, Ling Ma, James Brenton, Katherine Bell-McGuinn, Ana Oaknin, Alexandra Leary, Elaina Mann, Heidi Giordano, Mitch Rapon, Iain McNeish, Scott H. Kaufmann. BRCA1 and RAD51C Promoter Hypermethylation Confer Sensitivity to PARP Inhibitors in Patients with Platinum Sensitive Ovarian Carcinoma [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP28.

Abstract A11: NGS-based tumor genomic profiling to identify ovarian cancer patients who benefit from the PARP inhibitor rucaparib.

Background: PARP inhibitors (PARPi) are synthetically lethal to tumor cells with homologous recombination deficiency (HRD). HRD can result from deleterious BRCA1/2 mutations (BRCAmut) or other mechanisms that have not been fully elucidated. Regardless of mechanism, HRD leads to a common phenotype of genome-wide loss of heterozygosity (LOH). It has been hypothesized that this genomic phenotype can be used to identify BRCA wild-type (BRCAwt) HRD tumors likely sensitive to PARPi. Using comprehensive next generation sequencing (NGS)-based tumor genomic profiling, we developed an HRD assay for potential use as a companion diagnostic for rucaparib in high-grade ovarian cancer (HGOC) by combining tumor BRCA1/2 status and quantification of genomic LOH. Methods: In the phase 2 study ARIEL2 Part 1 (NCT01891344), pre-treatment screening biopsies and archival formalin-fixed paraffin embedded tumor specimens were profiled using Foundation Medicine9s NGS-based HRD assay, which detects all classes of genomic alterations, including base substitutions, insertions/deletions, and homozygous deletions in BRCA1/2. Genomic LOH was assessed by sequencing >3,500 evenly-distributed single nucleotide polymorphisms across the genome and quantifying the extent of genomic LOH. A pre-specified genomic LOH cutoff was determined using publicly available SNP array data of ovarian tumors to predict platinum sensitivity as a surrogate marker for PARPi sensitivity. Response was assessed by RECIST v1.1 and GCIG CA-125 response criteria. Results: As of July 1 2015, 195 archival tumor and 152 screening biopsy samples (142 matched pairs) from 206 HGOC patients enrolled (204 patients treated) in ARIEL2 Part 1 were successfully profiled using the NGS-based HRD assay. Some screening biopsies were not suitable for successful NGS-based HRD assessment primarily because of insufficient tumor nuclei or inadequate tumor volume. Most matched pairs of archival and pre-trial screening samples exhibited similar genomic LOH profiles (r=0.86); however, 14% of screening samples had higher genomic LOH compared with archival samples collected more than one year earlier. All BRCA1/2 germline and somatic mutated tumors had high genomic LOH in the screening samples. Receiver operating characteristic analysis of genomic LOH showed utility in identifying RECIST/CA-125 responders to rucaparib (AUC=0.72, p Conclusions: We developed an NGS-based HRD assay that assesses tumor BRCA1/2 and genomic LOH to prospectively identify HGOC patients who may benefit from rucaparib treatment. The optimized NGS-based HRD assay will be prospectively tested in the ongoing portion of the phase 2 study (ARIEL2 Part 2, NCT01891344) and a phase 3 maintenance study (ARIEL3, NCT01968213) that will investigate rucaparib in HGOC. Citation Format: Iain A. McNeish, Kevin K. Lin, James X. Sun, Sandra Goble, Amit Oza, Robert L. Coleman, Clare L. Scott, Gottfried Konecny, Anna V. Tinker, David M. O9Malley, Rebecca Kristeleit, Ling Ma, James D. Brenton, Katherine Bell-McGuinn, Ana Oaknin, Alexandra Leary, Elaina Mann, Heidi Giordano, Roman Yelensky, Mitch Raponi, Elizabeth Swisher. NGS-based tumor genomic profiling to identify ovarian cancer patients who benefit from the PARP inhibitor rucaparib. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A11.