HR Deficiency & Response to PARPi Therapy | Rubraca® (rucaparib) tablets

Up to 60% of your patients with ovarian cancer may be HR deficient1,2

All high grade serous ovarian cancer1,2

  • Up to 60% of patients with ovarian cancer may be HR-deficient, potentially improving their response to PARPi therapy1-4
  • In the U.S. alone >13,500 women diagnosed with ovarian cancer this year may be HR deficient1-5*

Homologous recombination (HR) is an important DNA rescue pathway3,4

  • A mutation in BRCA or another HR gene may result in HR deficiency and defects in DNA repair, a hallmark of cancer
  • Many of your patients with ovarian cancer may be HR deficient, potentially improving their response to Rubraca

Rubraca inhibits PARP-1, 2, and 36,7

PARP-1, 2, and 3 are enzymes that play an important role in DNA repair

Rubraca mechanism of action6,8

Cytotoxicity induced by rucaparib may involve*:

  • Inhibition of PARP enzymatic activity
  • Formation of PARP-DNA complexes (PARP-trapping) which prevents DNA damage repair

HR deficiency confers greater sensitivity to PARP inhibitors1,2

In normal cells, HR plays a role in repair of damaged DNA8

  • HR is nonfunctional in cells with HR deficiency, such as a mutation or alteration in BRCA or another HR gene
  • HR deficiency, may potentially improve response to PARP inhibitors
  • Rubraca plus HR deficiency may result in synthetic lethality6,7

 

*Based on 60% of estimated incidence for 2019 from the National Cancer Institute SEER Statistics.
BRCA=BRCA-mutation; BRCAwt=BRCA wildtype or non-mutated.

HR Deficiency Causes Genomic Instability, a Hallmark of Cancer3,4,9

HR is the main DNA rescue pathway and repairs double-strand DNA breaks

  • The HR pathway includes many cellular factors, such as BRCA1/2
  • A mutation or alteration in BRCA or another gene coding for HR factor results in HR deficiency (HRD) and compromised DNA repair, accumulation of alterations, and subsequent tumorigenesis

Commonly altered biomarkers resulting in HRD3,4,9,10

Test for HR deficiency for a more informed treatment plan11

  • No added testing burden, when using a next-generation sequencing (NGS) assay that can simultaneously report BRCA1/2 and HR status (eg, FoundationOne CDx)1,2

 

*Based on 60% of estimated incidence for 2019 from the National Cancer Institute SEER Statistics.

BRCA=BRCA-mutation; BRCAwt=BRCA wildtype or non-mutated; HRD=homologous recombination deficiency; HRD+=homologous recombination deficiency positive; HRD-=homologous recombination deficiency negative.

INDICATIONS

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

  • for the treatment of adult patients with 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

Read full ISI

Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) occur uncommonly in patients treated with Rubraca, and are potentially fatal adverse reactions. In approximately 1100 treated patients, MDS/AML occurred in 12 patients (1.1%), including those in long term follow-up. Of these, 5 occurred during treatment or during the 28 day safety follow-up (0.5%). The duration of Rubraca treatment prior to the diagnosis of MDS/AML ranged from 1 month to approximately 28 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 (see Dosage and Administration (2.2) in full Prescribing Information) 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 laboratory abnormalities in ARIEL3 (≥ 25%; Grade 1-4) were increase in creatinine (98%), decrease in hemoglobin (88%), increase in cholesterol (84%), increase in alanine aminotransferase (ALT) (73%), increase in aspartate aminotransferase (AST) (61%), decrease in platelets (44%), decrease in leukocytes (44%), decrease in neutrophils (38%), increase in alkaline phosphatase (37%), and decrease in lymphocytes (29%).

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%).

Most common laboratory abnormalities in Study 10 and ARIEL2 (≥ 35%; Grade 1-4) were increase in creatinine (92%), increase in alanine aminotransferase (ALT) (74%), increase in aspartate aminotransferase (AST) (73%), decrease in hemoglobin (67%), decrease in lymphocytes (45%), increase in cholesterol (40%), decrease in platelets (39%), and decrease in absolute neutrophil count (35%).

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.

You may report side effects to the FDA at 1‑800‑FDA‑1088 or www.fda.gov/medwatch. 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).

Please see full Prescribing Information for additional Important Safety Information.

 

References: 1. Mukhopadhyay A, et al. Cancer Res. 2012; 72(22):5675–5682. 2. Mukhopadhyay A, et al. Clin Cancer Res. 2010;16(8):2344-2351. 3. Chartron E, et al. Crit Rev Oncol Hematol. 2019;133:58-73. 4. Konstantinopolous PA, et al. Cancer Discov. 2015;5(11):1137-1154. 5. NCI. SEER cancer stat facts: ovarian cancer. 6. Rubraca [prescribing information]. Boulder, CO; Clovis Oncology. 7. Rimar KJ, et al. Cancer. 2017;123(11):1912-1924. 8. Iglehart JD, et al. N Engl J Med. 2009;361(2):189-191. 9. TCGA. Nature. 2011;474(7353):609-615. 10. Coleman RL, et al. Online supplementary appendix. Lancet. 2017. 11. FDA. https://www.fda.gov/medical-devices/recently-approved-devices/foundationone-cdx-p170019. Accessed November 26, 2019.

INDICATIONS

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

  • for the treatment of adult patients with 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

Read full ISI

Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) occur uncommonly in patients treated with Rubraca, and are potentially fatal adverse reactions. In approximately 1100 treated patients, MDS/AML occurred in 12 patients (1.1%), including those in long term follow-up. Of these, 5 occurred during treatment or during the 28 day safety follow-up (0.5%). The duration of Rubraca treatment prior to the diagnosis of MDS/AML ranged from 1 month to approximately 28 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 (see Dosage and Administration (2.2) in full Prescribing Information) 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 laboratory abnormalities in ARIEL3 (≥ 25%; Grade 1-4) were increase in creatinine (98%), decrease in hemoglobin (88%), increase in cholesterol (84%), increase in alanine aminotransferase (ALT) (73%), increase in aspartate aminotransferase (AST) (61%), decrease in platelets (44%), decrease in leukocytes (44%), decrease in neutrophils (38%), increase in alkaline phosphatase (37%), and decrease in lymphocytes (29%).

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%).

Most common laboratory abnormalities in Study 10 and ARIEL2 (≥ 35%; Grade 1-4) were increase in creatinine (92%), increase in alanine aminotransferase (ALT) (74%), increase in aspartate aminotransferase (AST) (73%), decrease in hemoglobin (67%), decrease in lymphocytes (45%), increase in cholesterol (40%), decrease in platelets (39%), and decrease in absolute neutrophil count (35%).

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.

You may report side effects to the FDA at 1‑800‑FDA‑1088 or www.fda.gov/medwatch. 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).

Please see full Prescribing Information for additional Important Safety Information.