Clovis Oncology Presents Data from Phase 2 Studies of Rucaparib in Advanced Ovarian Cancer and Pancreatic Cancer at 2016 ASCO Annual Meeting
“We are pleased to present our mature dataset from Part 1 of the ARIEL2
study for rucaparib in ovarian cancer at
Study objectives of the global, two-part single-arm open-label ARIEL2
trial in patients with advanced ovarian cancer include determining
rucaparib activity in prospectively defined molecular subgroups through
the assessment of progression-free survival (PFS) in patients with
tumors that have germline and somatic BRCA mutations, those with a
BRCA-like signature (patients whose tumors have other DNA repair
deficiencies, including those with high genomic LOH but with normal BRCA
genes (BRCAwt/LOHhigh)), and patients whose tumors
are biomarker negative (those with low genomic LOH, or BRCAwt/LOHlow).
Objective response rate (ORR), safety and pharmacokinetics were also
analyzed. Patients in ARIEL2 were treated with the recommended phase 2
dose (RP2D) of 600mg twice daily (BID). ARIEL2 Part 1 was initiated in
A NGS-based assay developed with
Updated Results of ARIEL2 Part 1
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.
An analysis of platinum-sensitive patients from ARIEL2 Part 1 identified a refined LOH cutoff of ≥16% that provided further discrimination of PFS, objective response rate and duration of response in patients with LOHhigh and LOHlow tumors who received a median of one prior treatment regimen. Using the refined LOH cutoff of ≥16%, patients in the BRCAmut subgroup demonstrated a 75 percent reduction in the risk of progression, and patients in the BRCAwt/LOHhigh subgroup demonstrated a 49 percent reduction in the risk of progression, both compared to the BRCAwt/LOHlow subgroup (hazard ratio: 0.25 [95% CI: 0.15, 0.42; p<0.001] and hazard ratio: 0.51 [95% CI: 0.34, 0.74; p<0.001], respectively). Median PFS for the BRCAmut, BRCAwt/LOHhigh, and BRCAwt/LOHlow subgroups was 12.8 months, 7.2 months and 5.0 months, respectively.
The confirmed investigator-assessed ORR based on RECIST criteria was significantly higher in the BRCAmut subgroup than in the BRCAwt/LOHlow with the prespecified LOH cutoff. As expected, the most robust clinical responses were observed in patients with tumor (germline and somatic) BRCA mutations: 80 percent (32/40) of BRCAmut patients achieved a response. Responses were observed in both germline and somatic BRCAmut tumors, including 85 percent (17/20) of patients with a gBRCA mutation and 74 percent (14/19) of patients with a sBRCA mutation. One patient with a BRCA mutation was indeterminate for mutation type. In the BRCAwt/LOHhigh subgroup, the ORR was 29 percent (24/82) and 33 percent (23/69) based on the prespecified and refined cutoff, respectively. In the BRCAwt/LOHlow subgroup, the ORR was 10 percent for both the prespecified and refined cutoffs, representing responses in 7 of 70 and 8 of 83 patients, respectively. Median duration of response for the prespecified and refined LOH cutoffs for the BRCAmut and BRCAwt/LOHhigh subgroups were the same at 9.2 months and 10.8 months, respectively, and highly similar for the BRCAwt/LOHlow subgroup at 5.6 months and 5.5 months, respectively.
The most common treatment-emergent AEs reported in ≥20 percent of all patients included nausea (80%), asthenia/fatigue (78%), constipation (46%), vomiting (44%) and dysgeusia (43%). These events were mostly Grade 1/2. The most common Grade 3/4 treatment-emergent AEs were anemia/decreased hemoglobin (21%) and ALT/AST elevations (12%). No treatment-related deaths were reported. Nineteen patients (9%) discontinued treatment because of an adverse event.
These results support the predictive utility of an HRD signature to identify patients with platinum-sensitive ovarian cancer who may benefit from rucaparib treatment. The NGS-based HRD assay will be prospectively applied to assess the utility of a rucaparib treatment-based LOHhigh cutoff in predicting response to rucaparib in the phase 3 ARIEL3 study investigating rucaparib in the maintenance setting in platinum-sensitive ovarian cancer.
Feasibility of Monitoring Response to Rucaparib with ctDNA
A study at the
Final Results of RUCAPANC
The open-label phase 2 RUCAPANC study investigated the safety and efficacy of rucaparib in patients with advanced pancreatic cancer and a known deleterious germline or somatic BRCA mutation and final results were presented in a poster session on
The ARIEL (Assessment of Rucaparib in Ovarian Cancer Trial) program is a novel, integrated translational-clinical program designed to accurately and prospectively identify ovarian cancer patients with tumor genotypes associated with benefit from rucaparib therapy.
- ARIEL2 is a two-part single-arm open label study. Part 1 is in platinum-sensitive patients designed to identify pre-specified tumor characteristics that predict sensitivity to rucaparib using DNA sequencing to evaluate each patient’s tumor and updated results are described above. Part 2, also referred to as the ARIEL2 Extension, is enrolling up to 300 patients with advanced ovarian cancer who have received at least three prior chemotherapy regimens and includes platinum-sensitive, -resistant and -refractory patients. It will evaluate clinical response in patients classified into molecularly-defined subgroups, including gBRCA-mutant, sBRCA-mutant and the BRCA-like signature by a prospectively defined genomic signature.
- The phase 2 portion of Study 10, the initial dose finding study, enrolled patients with relapsed, high-grade ovarian cancer associated with a deleterious germline BRCA mutation who have received 2-4 prior lines of chemotherapy.
- The ARIEL3 pivotal study is a randomized, double-blind study comparing the effects of rucaparib against placebo to evaluate whether rucaparib given as a maintenance therapy to platinum-sensitive patients can extend the period of time for which the disease is controlled after a positive outcome with platinum-based chemotherapy. Patients are randomized to receive either placebo or rucaparib and the primary endpoint of the study is PFS. The primary efficacy analysis will evaluate, in a step-down process, BRCA-mutant patients, all patients with a BRCA-like signature (including BRCA and non-BRCA), and then all patients.
- The ARIEL4 confirmatory study is expected to begin during the second half of 2016, and will compare treatment with rucaparib vs chemotherapy in relapsed ovarian cancer patients with BRCA mutations. The primary endpoint of the study is PFS.
- In addition to the ARIEL program in ovarian cancer, the Company is exploring rucaparib in other solid tumor types with significant BRCA and BRCA-like populations, including a pivotal prostate cancer study expected to initiate during the second half of 2016.
- Multiple combination studies are planned to initiate in the second half of 2016, including with inhibitors of PD-L1.
- For more information, please visit www.arielstudy.com.
Subgroup analysis of later-line BRCA-mutant patients from ARIEL2 Parts 1
and 2 and Study 10 will form the basis of rucaparib’s rolling New Drug
Application (NDA) to the U.S.
The NDA submission is expected to complete by the end of Q2 2016, and a
European Marketing Authorization Application (MAA) to the
The poster presentation, titled “RUCAPANC: An open-label, phase 2 trial of the PARP inhibitor rucaparib in patients (pts) with pancreatic cancer (PC) and a known deleterious germline or somatic BRCA mutation” was presented Saturday by
The poster presentation, titled “Refinement of prespecified cutoff
for genomic loss of heterozygosity (LOH) in ARIEL2 part 1: A phase II
study of rucaparib in patients (pts) with high grade ovarian carcinoma
(HGOC)” is being presented today by
The poster presentation, titled “Feasibility of monitoring response
to the PARP inhibitor rucaparib with targeted deep sequencing of
circulating tumor DNA (ctDNA) in women with high grade serous carcinoma
on the ARIEL2 trial” is being presented today by
The poster presentations will be available online at http://clovisoncology.com/products-companion-diagnostics/scientific-presentations/ as of the time of their scheduled presentation at the meeting.
Rucaparib is an oral, potent small molecule inhibitor of PARP1, PARP2 and PARP3 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) commonly referred to as “BRCA-like." Clovis is also exploring rucaparib in other solid tumor types with significant BRCA and BRCA-like populations, including prostate, breast and gastroesophageal cancers. Rucaparib was granted Breakthrough Therapy designation by the U.S.
About Clovis Oncology
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