On June 6, 2022 Clovis Oncology, Inc. (NASDAQ: CLVS) reported the first presentation of data from the monotherapy arm of the randomized, Phase 3 ATHENA (GOG-3020/ENGOT-ov45) trial (ATHENA-MONO) as a late-breaking oral abstract (LBA5500) to be presented on Monday, June 6, at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (Press release, Clovis Oncology, JUN 6, 2022, View Source [SID1234615632]). The data demonstrate that Rubraca as first-line maintenance treatment significantly improved investigator-assessed progression-free survival (PFS) compared with placebo in women with advanced ovarian cancer irrespective of biomarker status. The results were simultaneously published in the Journal of Clinical Oncology and are available starting at 9:00 a.m. EDT on June 6.
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"The results from the monotherapy portion of the Phase 3 ATHENA trial (ATHENA-MONO), demonstrate that eligible patients with advanced ovarian cancer who previously responded to platinum based chemotherapy can benefit from first-line maintenance treatment with rucaparib, regardless of their biomarker status," said Bradley J. Monk, MD, FACOG, FACS, at GOG Foundation, HonorHealth Research Institute, University of Arizona College of Medicine, Creighton University School of Medicine, Phoenix, AZ and global primary investigator of the ATHENA trial. "Currently, the optimal first-line maintenance strategy for treating newly diagnosed advanced ovarian cancer remains unclear, demonstrating the need for treatment advances in this setting."
"The data from the ATHENA-MONO portion of the trial validate the use of rucaparib for the first-line maintenance treatment of advanced ovarian cancer regardless of BRCA mutation and HRD status," said Rebecca S. Kristeleit, MD, PhD, of Guy’s and St Thomas’ NHS Foundation Trust in London and lead ENGOT/NCRI National Cancer Research Institute (View Source) investigator of the ATHENA trial. "Rucaparib significantly improved progression-free survival in all populations randomized, with median PFS in the rucaparib arm more than double that observed in the placebo arm of the trial."
Dr. Monk will present "ATHENA-MONO (GOG-3020/ENGOT-ov45): A randomized, double-blind, phase 3 trial evaluating rucaparib monotherapy versus placebo as maintenance treatment following response to first-line platinum-based chemotherapy in ovarian cancer" from 9:00 – 9:12 a.m. EDT during an Oral Abstract Session focused on gynecologic cancer that will be held from 9:00 a.m. – noon EDT on Monday, June 6. Building on the topline primary results previously announced, the presentation will feature an expanded description of the ATHENA-MONO study results including Kaplan-Meier curves and key secondary endpoints including PFS results by blinded independent centralized review (BICR) and other analyses. The presentation can also be viewed at View Source starting at 8:00 a.m. EDT on June 6.
ATHENA is a double-blind, placebo-controlled, Phase 3 trial of rucaparib in first-line ovarian cancer maintenance treatment. It has two parts which are statistically independent. The results presented at ASCO (Free ASCO Whitepaper) are from the ATHENA-MONO part (rucaparib versus placebo), with results from the ATHENA-COMBO part (rucaparib plus nivolumab versus rucaparib) expected in Q1 2023.
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) 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.
Significant Improvement in PFS in the HRD-Positive Patient Population
For the primary endpoint of PFS by investigator review in the HRD-positive patient population, the rucaparib arm (n=185) showed statistically significant improvement over the placebo arm (n=49) with a hazard ratio of 0.47 (95% CI: 0.31-0.72) representing a 53 percent reduction in the risk of disease progression. The median PFS for the HRD-positive patient population treated with rucaparib was 28.7 months compared to 11.3 months among those who received placebo (p=0.0004).
For the secondary endpoint of PFS by blinded independent central review (BICR) in the HRD-positive patient population, the rucaparib arm showed statistically significant improvement over the placebo arm with a hazard ratio of 0.44 (95% CI: 0.28-0.70) representing a 56 percent reduction in the risk of disease progression. The median PFS for the HRD-positive population treated with rucaparib was not reached compared to 9.9 months among those who received placebo (p=0.0004).
Significant Improvement in PFS in All Patients Studied (ITT or all patients randomized)
For the primary endpoint of PFS by investigator review in the ITT or all patients randomized population, the rucaparib arm (n=427) showed statistically significant improvement over the placebo arm (n=111) with a hazard ratio of 0.52 (95% CI: 0.40-0.68) representing a 48 percent reduction in the risk of disease progression. The median PFS for all patients randomized in ATHENA-MONO and treated with rucaparib was 20.2 months compared to 9.2 months among those who received placebo (p<0.0001).
For the secondary endpoint of PFS by BICR in the ITT or all patients randomized population, the rucaparib arm showed statistically significant improvement over the placebo arm with a hazard ratio of 0.47 (95% CI: 0.36-0.63; p<0.0001) representing a 53 percent reduction in the risk of disease progression. The median PFS for all patients randomized in ATHENA-MONO and treated with rucaparib was 25.9 months compared to 9.1 months among those who received placebo (p<0.0001).
Treatment Benefit in Exploratory Subgroups
In the exploratory subgroups studied, rucaparib demonstrated treatment benefit versus placebo regardless of BRCA mutation and HRD status.
HRD-positive BRCA-mutant Subgroup:
For PFS by investigator review, the rucaparib arm (n=91) demonstrated benefit over the placebo arm (n=24) with a hazard ratio of 0.40 (95% CI: 0.21-0.75) representing a 60 percent reduction in the risk of disease progression. The median PFS was not reached for those treated with rucaparib compared to 14.7 months for those who received placebo.
For PFS by BICR, the rucaparib arm demonstrated benefit over the placebo arm with a hazard ratio of 0.48 (95% CI: 0.23-1.00) representing a 52 percent reduction in the risk of disease progression. The median PFS for the HRD-positive BRCA-mutant subgroup in ATHENA-MONO was not reached for those treated with rucaparib or those who received placebo.
HRD-positive BRCA Wild-type/LOH-high Subgroup:
For PFS by investigator review, the rucaparib arm (n=94) demonstrated benefit over the placebo arm (n=25) with a hazard ratio of 0.58 (95% CI: 0.33-1.01) representing a 42 percent reduction in the risk of disease progression. The median PFS was 20.3 months for those treated with rucaparib compared to 9.2 months for those who received placebo.
For PFS by BICR, the rucaparib arm demonstrated benefit over the placebo arm with a hazard ratio of 0.46 (95% CI: 0.26-0.81) representing a 54 percent reduction in the risk of disease progression. The median PFS was 27.8 months for those treated with rucaparib compared to 9.1 months for those who received placebo.
HRD-negative BRCA Wild-type/LOH-low Subgroup:
For PFS by investigator review, the rucaparib arm (n=189) demonstrated benefit over the placebo arm (n=49) with a hazard ratio of 0.65 (95% CI: 0.45-0.95) representing a 35 percent reduction in the risk of disease progression. The median PFS was 12.1 months for those treated with rucaparib compared to 9.1 months for those who received placebo.
For PFS by BICR, the rucaparib arm demonstrated benefit over the placebo arm with a hazard ratio of 0.60 (95% CI: 0.40-0.89) representing a 40 percent reduction in the risk of disease progression. The median PFS was 12.0 months for those treated with rucaparib compared to 6.4 months for those who received placebo.
BRCA Wild-type LOH Status Unknown Subgroup:
For PFS by investigator review, the rucaparib arm (n=53) demonstrated benefit over the placebo arm (n=13) with a hazard ratio of 0.39 (95% CI: 0.20-0.78) representing a 61 percent reduction in the risk of disease progression. The median PFS was 17.5 months for those treated with rucaparib compared to 8.9 months for those who received placebo.
For PFS by BICR, the rucaparib arm demonstrated benefit over the placebo arm with a hazard ratio of 0.33 (95% CI: 0.16-0.68) representing a 67 percent reduction in the risk of disease progression. The median PFS was 17.4 months for those treated with rucaparib compared to 6.5 months for those who received placebo.
Summary of ORR and DoR
Among the HRD patient population, 17 patients in the rucaparib arm had measurable disease at baseline, 10 patients had confirmed ORR (overall response rate) per RECIST criteria (ORR: 10/17 [58.8%]; 95% CI: 32.9-81.6) compared to one in the placebo arm with measurable disease (ORR: 1/5 [20.0%]; 95% CI: 0.5-71.6). Ten patients treated with rucaparib experienced a partial response, compared to one patient in the placebo arm.
In the ITT population, 41 patients in the rucaparib arm had measurable disease at baseline, 20 patients had confirmed ORR per RECIST criteria (ORR: 20/41 [48.8%]; 95% CI: 32.9-64.9) compared to 1 in the placebo arm with measurable disease (ORR: 1/11 [9.1%]; 95% CI: 0.2-41.3). Nineteen patients in the rucaparib arm had a partial response versus one in the placebo arm.
Additionally, the median duration of response for HRD-positive patients in the rucaparib treatment arm was 16.7 months (95% CI: 5.7-not reached) and 22.1 months (95% CI: 8.4-not reached) in the ITT population, compared to 5.5 months (95% CI not applicable, with only one responder) in the placebo arm.
The secondary endpoint overall survival (OS) remains immature. At visit cutoff, 24.7% of events had occurred. At the current maturity, the hazard ratios of the OS in ATHENA-MONO in the HRD-positive and ITT populations are 0.97 (95% CI: 0.43-2.19) and 0.96 (95% CI: 0.63-1.47), respectively.
Safety Profile of Rucaparib
The safety profile observed in ATHENA-MONO was consistent with both the current US and European labels for rucaparib. The most common (≥5%) treatment-emergent grade ≥3 adverse events (TEAEs) among all patients treated with rucaparib (n=425) in the ATHENA-MONO comparison were anemia or decreased hemoglobin (28.7%), neutropenia or neutrophil count decreased (14.6%), increased ALT/AST (10.6%), and thrombocytopenia or platelet count decreased (7.1%). AST/ALT elevations were not accompanied by significant changes in bilirubin and there were no reports of drug induced liver toxicity as defined by Hy’s Law. The discontinuation rate due to TEAEs was 11.8% for rucaparib-treated patients and 5.5% for the placebo arm; there were two deaths (0.5%) due to TEAEs for rucaparib-treated patients and zero for the placebo arm. Median treatment duration for the rucaparib arm was 14.7 months versus 9.9 months for the placebo arm. Myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) was reported by two patients in the rucaparib group (one MDS during treatment; one AML during long-term follow-up) and no patients in the placebo group.
More than 70% of patients continued to receive ≥500 mg BID (>80% starting dose) Rubraca through month 12. Changes from baseline in FACT-O TOI scores were similar between rucaparib and placebo in the ITT population.
"These results further confirm that patients with advanced ovarian cancer regardless of biomarker status can benefit from first-line maintenance treatment with Rubraca," said Patrick J. Mahaffy, President and CEO of Clovis Oncology. "We would like to thank all patients, caregivers and physicians who participated in this trial, the results of which we believe demonstrate the benefit Rubraca can offer to eligible women with advanced ovarian cancer in the first-line maintenance treatment setting."
As previously disclosed, Clovis is currently evaluating the timing of the planned sNDA and Type II variation submissions.
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 Indications
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.
Rubraca is indicated for the treatment of adult women with a deleterious BRCA mutation (germline and/or somatic)-associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or more chemotherapies. Select patients for therapy based on an FDA-approved companion diagnostic for Rubraca.
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 1146 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%).
Most common adverse reactions in Study 10 and ARIEL2 (≥ 20%; Grade 1-4) were nausea (77%), asthenia/fatigue (77%), vomiting (46%), anemia (44%), constipation (40%), dysgeusia (39%), decreased appetite (39%), diarrhea (34%), abdominal pain (32%), dyspnea (21%), and thrombocytopenia (21%).
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.
Please Click here for full Prescribing Information for Rubraca.
You may also report side effects to Clovis Oncology, Inc. at 1-415-409-7220 (US toll) or 1-844-CLVS-ONC (1-844-258-7662; US toll-free).
Rubraca (rucaparib) European Union (EU) including Northern Ireland, and Great Britain (GB) authorized use and Important Safety Information
Rubraca is indicated as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy.
Rubraca is indicated as monotherapy treatment of adult patients with platinum sensitive, relapsed or progressive, BRCA mutated (germline and/or somatic), high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have been treated with ≥2 prior lines of platinum-based chemotherapy, and who are unable to tolerate further platinum-based chemotherapy.
Efficacy of Rubraca as treatment for relapsed or progressive epithelial ovarian cancer (EOC), fallopian tube cancer (FTC), or primary peritoneal cancer (PPC) has not been investigated in patients who have received prior treatment with a PARP inhibitor. Therefore, use in this patient population is not recommended.
Summary warnings and precautions:
Hematological toxicity
During treatment with Rubraca, events of myelosuppression (anemia, neutropenia, thrombocytopenia) may be observed and are typically first observed after 8–10 weeks of treatment with Rubraca. These reactions are manageable with routine medical treatment and/or dose adjustment for more severe cases. Complete blood count testing prior to starting treatment with Rubraca, and monthly thereafter, is advised. Patients should not start Rubraca treatment until they have recovered from hematological toxicities caused by previous chemotherapy (CTCAE grade ≥1).
Supportive care and institutional guidelines should be implemented for the management of low blood counts for the treatment of anemia and neutropenia. Rubraca should be interrupted or dose reduced according to Table 1 (see Posology and Method of Administration [4.2] of the Summary of Product Characteristics [SPC]) and blood counts monitored weekly until recovery. If the levels have not recovered to CTCAE grade 1 or better after 4 weeks, the patient should be referred to a hematologist for further investigations.
MDS/AML
MDS/AML, including cases with fatal outcome, have been reported in patients who received Rubraca. The duration of therapy with Rubraca in patients who developed MDS/AML varied from less than 1 month to approximately 28 months.
If MDS/AML is suspected, the patient should be referred to a hematologist for further investigations, including bone marrow analysis and blood sampling for cytogenetics. If, following investigation for prolonged hematological toxicity, MDS/AML is confirmed, Rubraca should be discontinued.
Photosensitivity
Photosensitivity has been observed in patients treated with Rubraca. Patients should avoid spending time in direct sunlight because they may burn more easily during Rubraca treatment; when outdoors, patients should wear a hat and protective clothing, and use sunscreen and lip balm with sun protection factor of 50 or greater.
Gastrointestinal toxicities
Gastrointestinal toxicities (nausea and vomiting) are frequently reported with Rubraca and are generally low grade (CTCAE grade 1 or 2) and may be managed with dose reduction (refer to Posology and Method of Administration [4.2], Table 1 of the SPC) or interruption. Antiemetics, such as 5-HT3 antagonists, dexamethasone, aprepitant and fosaprepitant, can be used as treatment for nausea/vomiting and may also be considered for prophylactic (i.e. preventative) use prior to starting Rubraca. It is important to proactively manage these events to avoid prolonged or more severe events of nausea/vomiting which have the potential to lead to complications such as dehydration or hospitalization.
Embryofetal toxicity
Rubraca can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings from animal studies. In an animal reproduction study, administration of Rubraca to pregnant rats during the period of organogenesis resulted in embryo-fetal toxicity at exposures below those in patients receiving the recommended human dose of 600 mg twice daily (see Preclinical Safety Data [5.3] of the SPC).
Pregnancy/contraception
Pregnant women should be informed of the potential risk to a fetus. Women of reproductive potential should be advised to use effective contraception during treatment and for 6 months following the last dose of Rubraca (see section 4.6 of the SPC). A pregnancy test before initiating treatment is recommended in women of reproductive potential.
Click here to access the current EU SmPC (including for Northern Ireland). Click here to access the current GB SmPC.
Healthcare professionals should report any suspected adverse reactions via their national reporting systems.
About the ATHENA Clinical Trial
ATHENA (GOG 3020/ENGOT-ov45) (NCT03522246) is an international, randomized, double-blind, phase III trial consisting of two separate and fully independently powered study comparisons evaluating Rubraca monotherapy (ATHENA-MONO) and Rubraca in combination with nivolumab (ATHENA-COMBO) as maintenance treatment for patients with newly diagnosed advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer. ATHENA enrolled approximately 1000 patients across 24 countries, all women with newly diagnosed ovarian cancer who responded to their first-line chemotherapy. The trial completed accrual in 2020 and was conducted in association with the Gynecologic Oncology Group (GOG) in the US and the European Network of Gynaecological Oncological Trial groups (ENGOT) in Europe. GOG and ENGOT are the two largest cooperative groups in the US and Europe dedicated to the treatment of gynecological cancers.
ATHENA-MONO is evaluating the benefit of Rubraca monotherapy versus placebo in 538 women in this patient population. The primary efficacy analysis evaluated two prospectively defined molecular sub-groups in a step-down manner: 1) HRD-positive (inclusive of BRCA mutant) tumors, and 2) the intent-to-treat population, or all patients treated in ATHENA-MONO.
The ATHENA-COMBO portion of the trial, anticipated to readout in Q1 2023, is evaluating the magnitude of benefit of adding Opdivo (nivolumab) to Rubraca monotherapy in the ovarian cancer first-line maintenance treatment setting. ATHENA-COMBO is anticipated to be the first Phase 3 dataset to readout evaluating the combination of a PARP inhibitor and an immune checkpoint inhibitor as maintenance treatment following completion and response to front-line chemotherapy.
About Ovarian Cancer
Ovarian cancer is the eighth leading cause of cancer-related death among women worldwide. In 2020, GLOBOCAN estimated 314,000 women received a new diagnosis of ovarian cancer and approximately 207,200 women died from ovarian cancer. According to the American Cancer Society, an estimated more than 19,000 women will be diagnosed with ovarian cancer in the United States and there will be an estimated nearly 13,000 deaths from ovarian cancer in 2022. According to GLOBOCAN, an estimated 66,000 women in Europe are diagnosed each year with ovarian cancer, and ovarian cancer is among those cancers with the highest rate of deaths. According to the NIH National Cancer Institute, more than 75% of women are diagnosed with ovarian cancer at an advanced stage.
Despite recent advances in the therapeutic landscape of newly diagnosed ovarian cancer, advanced ovarian cancer is still considered incurable for the majority of patients, and the optimal treatment strategy has yet to be determined.i Although most respond initially to this treatment, 80% of patients with advanced ovarian cancer will have a recurrence and require subsequent therapies.ii
About Biomarkers in Ovarian Cancer
In the high-grade epithelial ovarian cancer setting, a patient’s tumor can be classified based on the genetic biomarker status: those with homologous recombination deficiencies, or HRD-positive, include those with a mutation of the BRCA gene (BRCAm), inclusive of germline and somatic mutations of BRCA, which represent approximately 25 percent of patientsiii,iv; and those with a range of genetic abnormalities other than BRCAm, which result in other homologous recombination deficiencies that represent an additional estimated 25 percent of patients (HRD-positive, BRCA wild-type)v; in addition, those whose test results show no deficiencies in homologous recombination repair (HRD-negative) represent the remaining approximate 50 percent of patients.vi