Clovis Oncology, Inc. (NASDAQ:CLVS), today announced results from a subgroup analysis of data from the monotherapy comparison of the randomized, Phase 3 ATHENA (GOG-3020/ENGOT-ov45) trial (ATHENA-MONO). These data showed that Rubraca as first-line maintenance treatment improved progression-free survival (PFS) versus placebo across disease risk subgroups including surgical outcome, response to first-line chemotherapy, and additional analyses in other subgroups. The data were presented by Rebecca S. Kristeleit, MD, PhD, of Guy’s and St. Thomas’ NHS Foundation Trust in London and lead ENGOT/NCRI National Cancer Research Institute (https://www.ncri.org.uk/) investigator of the ATHENA trial as a Mini Oral abstract at the European Society of Medical Oncology (ESMO) Congress 2022 in Paris.
“These additional results from the ATHENA-MONO analysis of the Phase 3 ATHENA trial demonstrate that rucaparib should be considered a new first-line maintenance treatment option for women with advanced ovarian cancer,” Dr. Kristeleit said. “In this analysis, rucaparib prolonged progression-free survival for patients with or without high risk factors for progression, irrespective of molecular characteristics, adding to our understanding of the efficacy of rucaparib in the broadest population of patients assessed in a clinical trial for first-line PARP inhibitor monotherapy.”
ATHENA is a double-blind, placebo-controlled, Phase 3 trial of Rubraca in first-line ovarian cancer maintenance treatment. It has two parts which are statistically independent. The results presented at ESMO are from the ATHENA-MONO part (Rubraca versus placebo), with results from the ATHENA-COMBO part (Rubraca plus nivolumab versus Rubraca) expected in Q1 2023.
“As further demonstrated by the additional data presented at ESMO, the ATHENO-MONO analysis continues to reinforce the potential of Rubraca as a first-line maintenance therapy for women with advanced ovarian cancer,” said Patrick J. Mahaffy, President and CEO of Clovis Oncology. “We remain grateful to the patients who participated in the trial and for the support of the clinical community familiar with these results.”
ATHENA-MONO enrolled 538 women with high-grade ovarian, fallopian tube, or primary peritoneal cancer. The primary efficacy analysis evaluated two prospectively defined molecular subgroups in a step-down manner: 1) homologous recombination deficiency (HRD)-positive (inclusive of BRCAm tumors and BRCAwt/LOH high tumors), and 2) all patients randomized (overall intent-to-treat population [ITT]) in ATHENA-MONO. The following exploratory subgroup analyses are included in the ESMO presentation:
PFS by Surgical Outcome
Patients who received Rubraca as maintenance therapy showed benefit regardless of surgical outcome, whether there was complete resection (R0) during cytoreductive surgery or not.
In HRD-positive patients:
Patients who had a complete resection following cytoreductive surgery (R0):
Rubraca (n=107), median PFS not yet reached (NR); placebo (n=33), median PFS of 22.1 months
Hazard ratio of 0.52 (95% [Confidence Interval] CI: 0.30-0.92)
Patients who did not have a complete resection following cytoreductive surgery (non-R0):
Rubraca (n=78), median PFS of 20.3 months; placebo (n=16), median PFS of 9.1 months
Hazard ratio of 0.29 (95% CI: 0.15-0.56)
Among the ITT population:
Patients who had a complete resection following cytoreductive surgery (R0):
Rubraca (n=263), median PFS of 25.1 months; placebo (n=73), median PFS of 12.0 months
Hazard ratio of 0.60 (95% CI: 0.43-0.84)
Patients who did not have a complete resection following cytoreductive surgery (non-R0):
Rubraca (n=164), median PFS of 13.9 months; placebo (n=38), median PFS of 6.4 months
Hazard ratio of 0.41 (95% CI: 0.27-0.62)
PFS by First-Line Chemotherapy Response
Similarly, patients treated with Rubraca as maintenance therapy showed benefit among all subgroups when evaluated against response per RECIST v1.1 at any time during first-line chemotherapy.
Among HRD-positive patients:
Patients who demonstrated a partial response to first-line chemotherapy:
Rubraca (n=33), median PFS of 14.8 months; placebo (n=9), median PFS of 9.1 months
Hazard ratio of 0.43 (95% CI: 0.18-1.02)
Patients who demonstrated a complete response to first-line chemotherapy:
Rubraca (n=38), median PFS of 25.8 months; placebo (n=4), median PFS NR
Hazard ratio of 0.41 (95% CI: 0.10-1.63)
Among the ITT population:
Patients who demonstrated a partial response to first-line chemotherapy:
Rubraca (n=76), median PFS of 12.2 months; placebo (n=22), median PFS of 6.4 months
Hazard ratio of 0.37 (95% CI: 0.21-0.65)
Patients who demonstrated a complete response to first-line chemotherapy:
Rubraca (n=73), median PFS of 15.6 months; placebo (n=11), median PFS of 6.4 months
Hazard ratio of 0.48 (95% CI: 0.23-1.03)
Additional Analyses in the ITT Population by Subgroup
Additional analyses in other subgroups based on baseline clinical characteristics, including FIGO stage, timing of surgery, and CA-125 levels, also demonstrated that patients treated with Rubraca experienced a progression-free survival benefit compared to those treated with placebo. Safety was similar between subgroups analyzed.
Dr. Kristeleit’s presentation, as well as other company-sponsored Rubraca data presented at ESMO, can be viewed at the time of presentation at https://www.clovisoncology.com/pipeline/scientific-presentations/.
Rubraca is not currently approved in the first-line ovarian cancer maintenance setting.
About Rubraca (rucaparib)
Rucaparib is an oral, small molecule inhibitor of PARP1, PARP2 and PARP3 being developed in multiple tumor types, including ovarian and metastatic castration-resistant prostate cancers, as monotherapy, and in combination with other anti-cancer agents. Exploratory studies in other tumor types are also underway.
Rubraca is an unlicensed medical product outside of the US and Europe.
Rubraca Ovarian Cancer US FDA Approved Indication
Rubraca is indicated for the maintenance treatment of adult women with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.
Select Important Safety Information
Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) have occurred in patients treated with Rubraca, and are potentially fatal adverse reactions. In 1,146 treated patients, MDS/AML occurred in 20 patients (1.7%), including those in long term follow-up. Of these, 8 occurred during treatment or during the 28 day safety follow-up (0.7%). The duration of Rubraca treatment prior to the diagnosis of MDS/AML ranged from 1 month to approximately 53 months. The cases were typical of secondary MDS/cancer therapy-related AML; in all cases, patients had received previous platinum-containing regimens and/or other DNA damaging agents.
Do not start Rubraca until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1). Monitor complete blood counts for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities (> 4 weeks), interrupt Rubraca or reduce dose and monitor blood counts weekly until recovery. If the levels have not recovered to Grade 1 or less after 4 weeks or if MDS/AML is suspected, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Rubraca.
Based on its mechanism of action and findings from animal studies, Rubraca can cause fetal harm when administered to a pregnant woman. Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Rubraca.
Most common adverse reactions in ARIEL3 (≥ 20%; Grade 1-4) were nausea (76%), fatigue/asthenia (73%), abdominal pain/distention (46%), rash (43%), dysgeusia (40%), anemia (39%), AST/ALT elevation (38%), constipation (37%), vomiting (37%), diarrhea (32%), thrombocytopenia (29%), nasopharyngitis/upper respiratory tract infection (29%), stomatitis (28%), decreased appetite (23%), and neutropenia (20%).
Co-administration of rucaparib can increase the systemic exposure of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, which may increase the risk of toxicities of these drugs. Adjust dosage of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, if clinically indicated. If co-administration with warfarin (a CYP2C9 substrate) cannot be avoided, consider increasing frequency of international normalized ratio (INR) monitoring.
Because of the potential for serious adverse reactions in breast-fed children from Rubraca, advise lactating women not to breastfeed during treatment with Rubraca and for 2 weeks after the last dose.
