Date: 2016-06-06
Type of information: Results
phase: 2
Announcement: presentation of results at the American Society of Clinical Oncology (ASCO) annual meeting, in Chicago
Company: Clovis Oncology (USA - CO)
Product: rucaparib
Action mechanism: enzyme inhibitor/PARP inhibitor. Rucaparib is an oral, small molecule inhibitor of PARP1, PARP2 and PARP3 currently being developed for the treatment of ovarian cancer, specifically in patients with tumors with BRCA mutations and other DNA repair deficiencies beyond BRCA, including those with high genomic loss of heterozygosity (LOH) also known as “BRCA-like." A MAA submission in Europe for an ovarian cancer treatment indication was submitted and accepted for review during the fourth quarter of 2016. In December 2016, the FDA has granted accelerated approval to Rubraca® for the treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer who have been treated with two or more prior chemotherapies. The company plans to submit data from the completed ARIEL3 trial to the FDA for an sNDA for a second line and later maintenance treatment indication.
Disease: ovarian cancer, fallopian tube cancer, primary peritoneal cancer
Therapeutic area: Cancer - Oncology
Country: ARIEL2 : Australia, Canada, France, Spain, UK, USA - ARIEL3: Australia,Belgium,Canada,France,Germany,Israel,Italy, New Zealand,Spain,UK,USA - ARIEL4: Brazil,Canada,Czechia,Hungary,Israel,Italy,Poland,Russian Federation,Spain,Ukraine,UK,USA
Trial
details:
Latest
news: • On June 19, 2017, Clovis Oncology announced topline data from the confirmatory phase 3 ARIEL3 trial of rucaparib, which successfully achieved the primary endpoint of improved progression-free survival (PFS) by investigator review in each of the three populations studied. PFS was also improved in the rucaparib group compared with placebo by blinded independent central review (BICR), a key secondary endpoint. Based on these findings, the Company plans to submit a supplemental New Drug Application (sNDA) within the next four months for a second-line and later maintenance treatment indication for all women with platinum-sensitive ovarian cancer who have responded to their most recent platinum therapy.
ARIEL3 enrolled 564 women with platinum-sensitive, high-grade ovarian, fallopian tube, or primary peritoneal cancer. The primary efficacy analysis evaluated three prospectively defined molecular sub-groups in a step-down manner: 1) tumor BRCA mutant (tBRCAmut) patients, inclusive of germline and somatic mutations of BRCA; 2) HRD-positive patients, including BRCA-mutant patients and BRCA wild-type with high loss of heterozygosity, or LOH-high patients; and, finally, 3) the intent-to-treat population, or all patients treated in ARIEL3. Following is a table and a summary of the primary efficacy analyses and selected exploratory PFS endpoints per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by each of investigator review, which was the primary analysis of ARIEL3, and independent review (BICR), a key secondary endpoint of the study.
Summary of Primary Efficacy Analyses and Selected Exploratory Endpoints for ARIEL3
ARIEL3
Analysis Population
PFS by Investigator Review
(Primary Endpoint)
PFS by Blinded Independent Central Review
(Key Secondary Endpoint)
Primary Analyses
Hazard Ratio
Median PFS (months)
Rucaparib vs. Placebo
Hazard Ratio
Median PFS (months)
Rucaparib vs. Placebo
tBRCAmut
(n=196)
0.23; p<0.0001
16.6 vs. 5.4
0.20; p<0.0001
26.8 vs. 5.4
HRD-positive
(n=354)
0.32; p<0.0001
13.6 vs. 5.4
0.34; p<0.0001
22.9 vs. 5.5
Intent-to-Treat
(n=564)
0.36; p<0.0001
10.8 vs. 5.4
0.35; p<0.0001
13.7 vs. 5.4
Exploratory Analyses
BRCAwt / HRD-positive
(n=158)
0.44; p<0.0001
9.7 vs. 5.4
0.55; p=0.0135
11.1 vs. 5.6
BRCAwt / HRD-negative (n=161)
0.58; p=0.0049
6.7 vs. 5.4
0.47; p=0.0003
8.2 vs. 5.3
The most robust clinical outcomes were observed among ARIEL3 patients with a germline or somatic BRCA mutation (n=196). By investigator review, the rucaparib arm successfully achieved statistical significance over the placebo arm for the primary endpoint of PFS with a hazard ratio of 0.23. The median PFS for the tBRCAmut patients treated with rucaparib was 16.6 months vs. 5.4 months among those who received placebo.
By independent review (BICR), the rucaparib arm improved PFS over the placebo arm with a hazard ratio of 0.20. The median PFS for the tBRCAmut patients treated with rucaparib was 26.8 months vs. 5.4 months among those who received placebo. Results were consistent for the germline BRCA (n=130) and somatic BRCA (n=56) populations.
Significant Improvement in PFS in the HRD-positive Patient Population: This population included patients with a germline or somatic mutation of BRCA, as well as those whose tumors were BRCA wild type (BRCAwt) but determined to be HRD positive as defined by a Foundation Medicine assay (n=354). By investigator review, the rucaparib arm successfully achieved statistical significance over the placebo arm for the primary endpoint of PFS with a hazard ratio of 0.32 (p<0.0001). The median PFS for the HRD-positive patients treated with rucaparib was 13.6 months vs. 5.4 months among those who received placebo.
By independent review (BICR), the rucaparib arm improved PFS over the placebo arm with a hazard ratio of 0.34 (p<0.0001). The median PFS for the HRD-positive patients treated with rucaparib was 22.9 months vs. 5.5 months among those who received placebo.
Significant Improvement in PFS in All Patients Studied: Rucaparib also showed statistical significance in all 564 patients enrolled in the study. By investigator review, the rucaparib arm successfully achieved statistical significance over the placebo arm for the primary endpoint of PFS with a hazard ratio of 0.36 (p<0.0001). The median PFS for all patients treated with rucaparib was 10.8 months vs. 5.4 months for those who received placebo.
By independent review (BICR), the rucaparib arm improved PFS over the placebo arm with a hazard ratio of 0.35 (p<0.0001). The median PFS for all patients enrolled in ARIEL3 and treated with rucaparib was 13.7 months vs. 5.4 months for those who received placebo.
Exploratory PFS Endpoint Achieved in BRCAwt/HRD-positive Subgroup : The exploratory PFS endpoint was achieved in the 158 patients identified as BRCAwt HRD positive. By investigator review, the rucaparib arm successfully achieved its endpoint over the placebo arm for the primary endpoint of PFS with a hazard ratio of 0.44 (p<0.0001). The median PFS for these patients treated with rucaparib was 9.7 months vs. 5.4 months for those who received placebo.
By independent review (BICR), the rucaparib arm improved PFS over the placebo arm with a hazard ratio of 0.55 (p=0.014). The median PFS for these patients treated with rucaparib was 11.1 months vs. 5.6 months for those who received placebo.
Exploratory PFS Endpoint Achieved in BRCAwt/HRD-negative Subgroup : The exploratory PFS endpoint was achieved in the 161 patients identified as BRCAwt and HRD negative. By investigator review, the rucaparib arm successfully achieved its endpoint over the placebo arm for the primary endpoint of PFS with a hazard ratio of 0.58 (p=0.0049). The median PFS for these patients treated with rucaparib was 6.7 months vs. 5.4 months for those who received placebo.
By independent review (BICR), the rucaparib arm improved PFS over the placebo arm with a hazard ratio of 0.47 (p=.0003). The median PFS for these patients treated with rucaparib was 8.2 months vs. 5.3 months for those who received placebo.
Exploratory Endpoint of Response Rate : Enrollment in ARIEL3 included one-third of patients who had achieved a complete response to their prior platinum-based therapy, and two-thirds of patients who had achieved a partial response to their prior platinum-based therapy. Of those with a partial response, 37% had measurable disease at the time of enrollment and were therefore evaluable for response. The confirmed overall response rate by investigator-assessed RECISTv1.1 in the tBRCAmut group treated with rucaparib was 38% (15/40), of these, 18% (7/40) were complete responses. This compared with 9% (2/23) in the placebo group (p=0.0055). No complete responses were seen in the tBRCAmut placebo group. RECIST responses were also observed in BRCA wild-type HRD-positive and BRCA wild-type HRD-negative subgroups.
RECIST responses were not assessed by independent blinded review.
Summary of ARIEL3 Safety : The most common (?5%) treatment-emergent grade 3/4 adverse events (TEAEs) among all patients treated with rucaparib in the ARIEL3 study were anemia/decreased hemoglobin (19%), ALT/AST increase (11%), asthenia/fatigue (7%), neutropenia (7%), and thrombocytopenia (5%).The discontinuation rate for TEAEs was 14% for rucaparib-treated patients and 2.6% for the placebo arm. The rate of treatment-emergent myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) in the rucaparib arm was <1% (3/372), and no patients on the placebo arm experienced treatment-emergent MDS/AML.
Clovis Oncology plans to provide an expanded description of the ARIEL3 results in a scientific session at a medical meeting later this year.
PFS: progression-free survival; tBRCAmut: tumor BRCA mutant; HRD: homologous recombination deficiency; BRCAwt: BRCA wild type
In 57 platinum-sensitive patients whose immediate prior therapy was platinum-based, the investigator-assessed ORR was 70% (95% CI: 57-72) for the overall population, with 83% (95% CI: 59-96), 86% (95% CI: 57-98) and 52% (95% CI: 31-72) ORR observed in patients treated with one, two, or three or more prior lines, respectively. The DCR in the same population was 81% (95% CI: 68-90) for the overall population, with 94% (95% CI: 73-100), 86% (95% CI: 57-98) and 68% (95% CI: 47-85) in patients treated with one, two, or three or more prior lines, respectively. The median PFS in the overall platinum-sensitive population whose immediate prior therapy was platinum-based was 12.7 months (95% CI: 9.0-14.7; 30% censoring).
In addition, PFS and ORR were assessed by BRCA mutation type in platinum-sensitive patients whose immediate prior treatment was platinum. Patients with a germline or somatic BRCA mutation had ORRs of 75% (95% CI: 57-89) and 74% (95% CI: 49-91), and median PFS of 12.8 and 12.7 months, respectively (95% CI: 8.9-16.6; 31% censoring and 6.2-18.2; 21% censoring). Patients with a BRCA mutation had ORRs of 71% (95% CI: 53-85) and 70% (95% CI: 47-87), and median PFS of 12.8 and 11.2 months, respectively (95% CI: 8.1-18.2; 26% censoring and 7.3-16.6; 35% censoring).
All evaluable platinum-resistant and -refractory patients had been treated with three or more lines of therapy. In 49 platinum-resistant patients, the ORR was 25% (95% CI: 13-39), the DCR was 39% (95% CI: 25-54), and the median PFS was 7.3 months (95% CI: 5.5-7.7; 27% censoring). In 14 platinum-refractory patients, there were no responders, consistent with data previously presented at the 2016 ESMO Annual Meeting. However, the DCR was 29% (95% CI: 8-58) and the median PFS was 5.0 months (95% CI: 1.9-5.7; 21% censoring).
The presentation also discussed the potential role of secondary somatic mutations restoring BRCA function as a mechanism of platinum resistance in patients with platinum-resistant or -refractory disease. Published data have shown that secondary mutations in BRCA are more frequently observed in platinum-resistant patients than platinum-sensitive patients. Data presented show that the presence of secondary somatic BRCA mutations may be a better predictor of rucaparib efficacy than prior responsiveness to platinum-based chemotherapy in patients with platinum-resistant or -refractory disease. In 55 evaluable patients with platinum-resistant or -refractory disease, those without a secondary somatic BRCA mutation (n=47) achieved a median PFS of 7.3 months (95% CI: 5.4-9.0; 26% censoring); conversely, eight patients with a secondary somatic mutation demonstrated a median PFS of only 1.7 months (95% CI: 1.6-3.2; 0% censoring). These secondary mutations were identified by sequencing of screening tumor biopsy and/or circulating tumor DNA (ctDNA) analysis.
The most common treatment-emergent adverse events observed in ARIEL2 included nausea (78%), asthenia/fatigue (78%), and vomiting (49%). The most common treatment-emergent grade 3/4 adverse events observed in ARIEL2 included anemia/decreased hemoglobin (29%), ALT/AST increased (10%), and asthenia/fatigue (10%). Treatment-emergent adverse events led to dose reductions in 49% of patients, and treatment discontinuation in 13% of patients.
The second presentation discussed an analysis of BRCA1 and RAD51C hypermethylation among archival and pretreatment biopsies from part 1 of the ARIEL2 study. The analysis demonstrated that, among ovarian cancer patients, methylation of BRCA1 and RAD51C is associated with high loss of heterozygosity (LOH), consistent with the HRD phenotype. Further, methylation of BRCA1 and RAD51C appear to confer sensitivity to rucaparib, as do mutations of CDK12. These data suggest that methylation is more reliably assessed in pretreatment than archival tumor samples. Dr. Swisher concludes that routine sequencing of high-grade ovarian cancer tumor tissue biopsies would identify at least 10-15% of women with a somatic mutation and 20% of women with a germline mutation whose tumors might be sensitive to rucaparib.
For the efficacy population (n=106), the median number of prior chemotherapies was three, with 39% having received two prior therapies and 61% of patients having received three or more prior therapies. The median number of prior platinum-based therapies was two, with 57% having received two prior platinum-based therapies, and 43% having received three or more prior platinum-based therapies. Seventy-five percent of patients in the efficacy population were platinum-sensitive (as defined by recurrence after progression free interval (PFI) of ?6 months), 19% were platinum resistant (recurrence after PFI <6 months) and 7% were platinum refractory (progression on platinum, PFI <2 months).
A NGS-based assay developed with Foundation Medicine, Inc. was used to determine the percentage of genomic LOH, mutations in BRCA, and other homologous recombination genes in archival tumor tissue and pretreatment biopsies for patients enrolled in ARIEL2. A prespecified cutoff of ?14% for LOHhigh was determined through analysis of microarray and survival data for patients in The Cancer Genome Atlas who had ovarian carcinoma and had received platinum-based chemotherapy. A planned post hoc analysis using outcome data from ARIEL2 Part 1 was performed to refine the genomic cutoff. The data for both the prespecified and refined cutoff percentages are presented in a poster presentation.
Data presented from the ARIEL2 Part 1 study demonstrated clinical activity in patients with tumors with germline and somatic BRCA mutations as well as those with tumors classified as BRCAwt/LOHhigh. Using the prespecified ?14% cutoff, patients in the BRCAmut subgroup demonstrated a 73 percent reduction in the risk of progression, and patients in the BRCAwt/LOHhigh subgroup demonstrated a 38 percent reduction in the risk of progression, both compared to the BRCAwt/LOHlow subgroup (hazard ratio: 0.27 [95% CI: 0.16, 0.44; p<0.001] and hazard ratio: 0.62 [95% CI: 0.42, 0.90; p=0.01], respectively). Median PFS for the BRCAmut, BRCAwt/LOHhigh, and BRCAwt/LOHlow subgroups was 12.8 months, 5.7 months and 5.2 months, respectively.
Feasibility of Monitoring Response to Rucaparib with ctDNA : A study at the University of Cambridge was conducted to assess TP53 mutant allele fraction (MAF) in circulating tumor DNA (ctDNA) from a subset of 18 patients in ARIEL2 Part 1 and will be presented in a poster session this afternoon. Plasma samples were collected from 18 patients in the ARIEL2 Part 1 study during screening, on day 1 of each cycle, and at the end of rucaparib treatment. The objective was to assess monitoring responses to rucaparib with targeted amplicon deep sequencing (TADS) of ctDNA. Seven of 9 patients with a >50% reduction of TP53 MAF in ctDNA at cycle 2 achieved a RECIST PR; this included 5/6 patients with either a germline or somatic BRCA mutation. No patients with a <50% reduction at cycle 2 (n=5) achieved a RECIST response. TADS detected different types of TP53 mutation in plasma including substitutions (n=12) and indels (n=6) across a wide spectrum of allele fractions (0.01–42.3%) with 100% concordance for TP53 mutation status in matched tumor-plasma samples. ctDNA is a potential biomarker for monitoring responses to the PARP inhibitor rucaparib.
The NDA submission is expected to complete by the end of Q2 2016, and a European Marketing Authorization Application (MAA) to the European Medicines Agency is planned for Q4 2016. Rucaparib was granted Breakthrough Therapy designation from the FDA in April 2015.
Following on the recent Breakthrough Therapy designation status of rucaparib by the FDA, data from the ARIEL2 study, if positive, are expected to form the basis of a planned new drug application (NDA) filing for treatment of advanced ovarian cancer in 2016.
The oral presentation, titled, “Results of ARIEL2: A Phase 2 trial to prospectively identify ovarian cancer patients likely to respond to rucaparib using tumor genetic analysis” has been presented on Monday, June 1 (Abstract 5508).
