ARIEL3 Efficacy

Rubraca Significantly Extended PFS
and Demonstrated Anti-Tumor Efficacy1-4

HR-deficient (HRd) PFS
HR-deficient (HRd) ORR
HR-proficient (HRp) PFS

In the HRd population, Rubraca demonstrated a statistically significant median PFS benefit of 13.6 months vs 5.4 months with placebo in 2La maintenance1,2

  • Rubraca more than doubled (2.5x) median PFS compared to placebo in the HRd population1
  • At one-year, 51% of patients on Rubraca were progression-free vs 12% on placebo3
  • IRR-assessed PFS (secondary endpoint, N=354)
    • Rubraca demonstrated a statistically significant median PFS benefit of 22.9 months vs 5.5 months with placebo (HR=0.34 [95% CI, 0.24-0.47]; P<0.0001)2
    • No multiplicity adjustment method for IRR PFS was specified in study protocol. At the time of PFS analysis, overall survival data were not mature (22% of events had occurred)1

HRd

Primary endpoint: Investigator-assessed PFS (N=354)b

Line chart of Rubraca trial results In the HR-deficient (HRd) population

Figure references.1-3,5,6

Among those with residual disease who were HRd, Rubraca further reduced the tumor burden with a confirmed response rate of 26% vs 7% with placebob-e,4

  • Rubraca demonstrated nearly 4 times (3.7x) higher ORR vs placebo in the HRd population
  • 66% of those that responded (26/39) achieved a complete response
  • 65% of all patients in ARIEL3 had residual disease
  • This analysis is exploratory in nature and does not control for Type 1 error rate.

HRd

Confirmed response rate

Bar chart of overall response rate (ORR) in HR-deficient (HRd) population among Rubraca patients

In the HRp population, at one-year, 32% of patients were progression-free on Rubraca (n=107) vs 4% on placebo (n=54)

HRp (HRd-)

Primary endpoint: Investigator-assessed PFS (N=161)a

Line chart of Rubraca trial results In the HR-proficient (HRp) population

Figure references.1-3,5,6

HR-deficient (HRd) PFS

In the HRd population, Rubraca demonstrated a statistically significant median PFS benefit of 13.6 months vs 5.4 months with placebo in 2La maintenance1,2

  • Rubraca more than doubled (2.5x) median PFS compared to placebo in the HRd population1
  • At one-year, 51% of patients on Rubraca were progression-free vs 12% on placebo3
  • IRR-assessed PFS (secondary endpoint, N=354)
    • Rubraca demonstrated a statistically significant median PFS benefit of 22.9 months vs 5.5 months with placebo (HR=0.34 [95% CI, 0.24-0.47]; P<0.0001)2
    • No multiplicity adjustment method for IRR PFS was specified in study protocol. At the time of PFS analysis, overall survival data were not mature (22% of events had occurred)1

HRd

Primary endpoint: Investigator-assessed PFS (N=354)b

Line chart of Rubraca trial results In the HR-deficient (HRd) population

Figure references.1-3,5,6

HR-deficient (HRd) ORR

Among those with residual disease who were HRd, Rubraca further reduced the tumor burden with a confirmed response rate of 26% vs 7% with placebob-e,4

  • Rubraca demonstrated nearly 4 times (3.7x) higher ORR vs placebo in the HRd population
  • 66% of those that responded (26/39) achieved a complete response
  • 65% of all patients in ARIEL3 had residual disease
  • This analysis is exploratory in nature and does not control for Type 1 error rate.

HRd

Confirmed response rate

Bar chart of overall response rate (ORR) in HR-deficient (HRd) population among Rubraca patients
HR-proficient (HRp) PFS

In the HRp population, at one-year, 32% of patients were progression-free on Rubraca (n=107) vs 4% on placebo (n=54)

HRp (HRd-)

Primary endpoint: Investigator-assessed PFS (N=161)a

Line chart of Rubraca trial results In the HR-proficient (HRp) population

Figure references.1-3,5,6

In the Overall Population, Rubraca Significantly Extended
PFS and Demonstrated Anti-Tumor Efficacy1,2

Overall Population PFS
Overall Population ORR

Rubraca demonstrated a statistically significant median PFS benefit of 10.8 months vs 5.4 months with placebo in 2La maintenance1,2

  • Rubraca more than doubled (2.5x) median PFS compared to placebo in the overall population1
  • IRR-assessed PFS (secondary endpoint, N=564)
    • Rubraca demonstrated a statistically significant median PFS benefit of 13.7 months vs 5.4 months with placebo (HR=0.35 [95% CI, 0.28-0.45]; P<0.0001)
    • No multiplicity adjustment method for IRR PFS was specified in study protocol. At the time of PFS analysis, overall survival data were not mature (22% of events had occurred).1

Overall Population

Primary endpoint: Investigator-assessed PFS (N=564)b

Line chart of Rubraca trial results In the overall population

Figure references.1-3,5,6

Rubraca further reduced the tumor burden in 2La maintenance treatment among those with residual disease (65% of all patients in ARIEL3 had residual disease)b-d,4

  • Rubraca demonstrated over 3 times (3.3x) higher ORR vs placebo in the overall populationb-d
  • This analysis is exploratory in nature and does not control for Type 1 error rate.

Overall Population

Confirmed response rate

Bar chart of the confirmed response rate in overall population among Rubraca patients
Overall Population PFS

Rubraca demonstrated a statistically significant median PFS benefit of 10.8 months vs 5.4 months with placebo in 2La maintenance1,2

  • Rubraca more than doubled (2.5x) median PFS compared to placebo in the overall population1
  • IRR-assessed PFS (secondary endpoint, N=564)
    • Rubraca demonstrated a statistically significant median PFS benefit of 13.7 months vs 5.4 months with placebo (HR=0.35 [95% CI, 0.28-0.45]; P<0.0001)
    • No multiplicity adjustment method for IRR PFS was specified in study protocol. At the time of PFS analysis, overall survival data were not mature (22% of events had occurred).1

Overall Population

Primary endpoint: Investigator-assessed PFS (N=564)b

Line chart of Rubraca trial results In the overall population

Figure references.1-3,5,6

Overall Population ORR

Rubraca further reduced the tumor burden in 2La maintenance treatment among those with residual disease (65% of all patients in ARIEL3 had residual disease)b-d,4

  • Rubraca demonstrated over 3 times (3.3x) higher ORR vs placebo in the overall populationb-d
  • This analysis is exploratory in nature and does not control for Type 1 error rate.

Overall Population

Confirmed response rate

Bar chart of the confirmed response rate in overall population among Rubraca patients

Rubraca Significantly Extended PFS and Demonstrated
Anti-Tumor Efficacy Regardless of BRCA Mutation Status1,2

BRCAmut+ PFS
BRCAmut+ ORR
BRCAwt, HRd PFS

In the BRCAmut+ population, Rubraca demonstrated a statistically significant median PFS benefit of 16.6 months vs 5.4 months with placebo in 2La maintenance1,2

  • Rubraca more than tripled (3.1x) median PFS compared to placebo in the BRCAmut+ population1
  • IRR-assessed PFS (secondary endpoint, N=196):
    • Rubraca demonstrated a statistically significant median PFS benefit of 26.8 months vs 5.4 months with placebo (HR=0.20 (95% CI, 0.13 - 0.32)2
    • No multiplicity adjustment method for IRR PFS was specified in study protocol. At the time of PFS analysis, overall survival data were not mature (22% of events had occurred).1

BRCAmut+

Primary endpoint: Investigator-assessed PFS (N=196)b

Line chart of Rubraca trial results In the BRCAmut+ population

Figure references.1-3,5,6

In the BRCAmut+ population, Rubraca further reduced the tumor burden in 2La maintenance treatment among those with residual diseaseb-d,4

  • Rubraca demonstrated over 4 times (4.5x) higher ORR vs placebo in the BRCAmut+ populationb-d
  • 65% of all patients in ARIEL3 had residual disease
  • This analysis is exploratory in nature and does not control for Type 1 error rate.

BRCAmut+

Confirmed response rate

Bar chart of overall response rate (ORR) by BRCAmut+ in Rubraca patients

In the BRCAwt, HRd Population, Rubraca demonstrated a statistically significant median PFS benefit of 9.7 months vs 5.4 months with placebo in 2La maintenance

  • Rubraca nearly doubled (1.8x) PFS compared to placebo in the BRCAwt, HRd population1
  • At one year, 41% of patients on Rubraca were progression-free vs. 11% on placebo3
  • IRR-assessed PFS (secondary endpoint, N=158)1:
    • Rubraca demonstrated a statistically significant median PFS benefit of 11.1 months vs 5.6 months with placebo (HR=0.55 [95% CI, 0.35-0.89]; P=0.0135)
    • No multiplicity adjustment method for IRR PFS was specified in study protocol. At the time of PFS analysis, overall survival data were not mature (22% of events had occurred)1

BRCAwt HRd

Investigator-assessed PFS (N=158)b

Line chart of Rubraca trial results In the BRCA wild-type (BRCAwt), HR-deficient (HRd) population

Figure references.1-3,5,6

BRCAmut+ PFS

In the BRCAmut+ population, Rubraca demonstrated a statistically significant median PFS benefit of 16.6 months vs 5.4 months with placebo in 2La maintenance1,2

  • Rubraca more than tripled (3.1x) median PFS compared to placebo in the BRCAmut+ population1
  • IRR-assessed PFS (secondary endpoint, N=196):
    • Rubraca demonstrated a statistically significant median PFS benefit of 26.8 months vs 5.4 months with placebo (HR=0.20 (95% CI, 0.13 - 0.32)2
    • No multiplicity adjustment method for IRR PFS was specified in study protocol. At the time of PFS analysis, overall survival data were not mature (22% of events had occurred).1

BRCAmut+

Primary endpoint: Investigator-assessed PFS (N=196)b

Line chart of Rubraca trial results In the BRCAmut+ population

Figure references.1-3,5,6

BRCAmut+ ORR

In the BRCAmut+ population, Rubraca further reduced the tumor burden in 2La maintenance treatment among those with residual diseaseb-d,4

  • Rubraca demonstrated over 4 times (4.5x) higher ORR vs placebo in the BRCAmut+ populationb-d
  • 65% of all patients in ARIEL3 had residual disease
  • This analysis is exploratory in nature and does not control for Type 1 error rate.

BRCAmut+

Confirmed response rate

Bar chart of overall response rate (ORR) by BRCAmut+ in Rubraca patients
BRCAwt, HRd PFS

In the BRCAwt, HRd Population, Rubraca demonstrated a statistically significant median PFS benefit of 9.7 months vs 5.4 months with placebo in 2La maintenance

  • Rubraca nearly doubled (1.8x) PFS compared to placebo in the BRCAwt, HRd population1
  • At one year, 41% of patients on Rubraca were progression-free vs. 11% on placebo3
  • IRR-assessed PFS (secondary endpoint, N=158)1:
    • Rubraca demonstrated a statistically significant median PFS benefit of 11.1 months vs 5.6 months with placebo (HR=0.55 [95% CI, 0.35-0.89]; P=0.0135)
    • No multiplicity adjustment method for IRR PFS was specified in study protocol. At the time of PFS analysis, overall survival data were not mature (22% of events had occurred)1

BRCAwt HRd

Investigator-assessed PFS (N=158)b

Line chart of Rubraca trial results In the BRCA wild-type (BRCAwt), HR-deficient (HRd) population

Figure references.1-3,5,6

Rubraca Improved PFS in Nearly All Patient Subgroups
Including Difficult-to-Treat Populations2

PFS observed in preplanned subgroup analysis2

Table with Rubraca data analysis on PFS observed in preplanned subgroups

  • Figure references.2,6
  • Adapted from: Coleman RL, et al. Lancet. 2017;390(10106):1949-1961.

  • No multiplicity adjustment for subgroup analyses was specified in the study protocol. This analysis is exploratory in nature and does not control for the Type 1 error rate.6

Safety & Tolerability

The majority of adverse reactions and lab abnormalities were Grades 1 or 21

SEE SAFETY PROFILE
  • aRubraca was studied in patients who had received at least 2 lines of chemotherapy.
  • bEvaluated according to RECIST v1.1.1,3,6
  • cNo disease=all patients who had no target lesions or non-target lesions at baseline.6
  • dPooled measurable and non-measurable disease at baseline.4
  • eTen patients could not be definitively assessed as germline or somatic (n=8 with Rubraca and n=2 with placebo).6
  • fTumor sample was not evaluable for percentage of genomic LOH due to low tumor content or aneuploidy.
  • gPrevious treatment with bevacizumab was permitted as part of penultimate or earlier treatment.
  • 2L, second-line; BRCA, breast cancer susceptibility gene; BRCAmut+, BRCA-mutation positive, which includes mutations in the BRCA1 and/or BRCA2 gene; BRCAwt, BRCA wild-type; CA125, cancer antigen 125; CI, confidence interval; CR, complete response; GCIG, Gynecologic Cancer InterGroup; HR, hazard ratio; HRd, homologous recombination-deficient; HRp, homologous recombination-proficient (HRd-); IRR, independent radiological review; LOH, loss of heterozygosity; ORR, objective response rate; PFS, progression-free survival; PR, partial response; RECIST v1.1, Response Evaluation Criteria in Solid Tumors. Version 1.1; rOC, recurrent ovarian cancer.

INDICATION

Rubraca is indicated for the maintenance treatment of adult patients 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 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%).

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 see full Prescribing Information for additional Important Safety Information.

References: 1. RUBRACA (rucaparib) tablets [package insert]. Boulder, CO: Clovis Oncology, Inc. 2. Coleman RL, Oza AM, Lorusso D, et al; ARIEL3 investigators. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390(10106):1949-1961. 3. Coleman RL, Oza AM, Lorusso D, et al; ARIEL3 investigators. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390(10106):1949-1961. Online supplementary appendix. 4. Clovis Oncology. 2-year PFS rates. Data on file. 5. Clovis Oncology. A multicenter, randomized, double-blind, placebo-controlled phase 3 study of Rucaparib as switch maintenance following platinum-based chemotherapy in patients with platinum-sensitive, high-grade serous or endometrioid epithelial ovarian, primary peritoneal or fallopian tube cancer. Clinical study report. 2017. Data on file. 6. Clovis Oncology. RF-ARIEL3. CRRs residual disease. July 10, 2019. Data on file.

INDICATION

Rubraca is indicated for the maintenance treatment of adult patients 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

Read full ISI

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%).

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 see full Prescribing Information for additional Important Safety Information.

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