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Understanding the Unmet Need in Ovarian Cancer

Watch Dr. Joshua Kesterson discuss the unmet need in ovarian cancer.

Watch Dr. Joshua Kesterson discuss the unmet need in ovarian cancer.

  • VIDEO TRANSCRIPT | 11:11

    ONSCREEN TEXT THAT APPEARS THROUGHOUT REMAINDER OF THE VIDEO:
    [ZEJULA logo]
    Please see Important Safety Information throughout this presentation. Please see the full Prescribing Information at zejulahcp.com

    ONSCREEN TEXT:
    Unmet Need in Ovarian Cancer

    ZEJULA is indicated for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy.

    Program sponsored by GSK. Speaker is contracted for this service. Information presented is consistent with FDA guidelines.

    ZEJULA. Prescribing Information. GlaxoSmithKline; 2021.

    JOSHUA KESTERSON:
    Hello. My name is Dr. Joshua Kesterson and today we will be discussing the unmet need in ovarian cancer in relation to ZEJULA capsules, also known as niraparib.
    ZEJULA is a once-daily oral poly (ADP-ribose) polymerase 1 and 2, more frequently referred to as PARP1 and PARP2, inhibitor indicated for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy.



    ONSCREEN TEXT:
    Important Safety Information:
    Myelodysplastic syndrome/acute myeloid leukemia

    JOSHUA KESTERSON:
    First, let’s discuss some important safety information for ZEJULA.



    ONSCREEN TEXT:
    Important Safety Information:
    Myelodysplastic syndrome/acute myeloid leukemia

    Myelodysplastic syndrome or acute myeloid leukemia (MDS/AML), including some fatal cases, was reported in 15 patients (0.8%) out of 1,785 patients treated with ZEJULA monotherapy in clinical trials

    • The duration of therapy in patients who developed secondary MDS/cancer therapy-related AML varied from 0.5 months to 4.9 years. These patients had received prior chemotherapy with platinum agents and/or other DNA-damaging agents including radiotherapy
    • Discontinue ZEJULA if MDS/AML is confirmed


    AML, acute myeloid leukemia; MDS, myelodysplastic syndrome.

    ZEJULA. Prescribing Information. GlaxoSmithKline; 2021.

    NARRATOR:
    Myelodysplastic syndrome or acute myeloid leukemia, which will be referred to hereafter as MDS or AML, including cases with fatal outcome, has been reported in patients who received ZEJULA monotherapy in clinical trials.

    In one thousand seven hundred eighty-five patients treated with ZEJULA in clinical trials, MDS or AML occurred in 15 patients, or 0.8%.

    The duration of therapy with ZEJULA in patients who developed secondary MDS or cancer therapy–related AML varied from 0.5 months to 4.9 years. These 15 patients had received previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy.

    Discontinue ZEJULA if MDS or AML is confirmed.



    ONSCREEN TEXT:
    Important Safety Information:
    Hematologic adverse reactions

    Hematologic adverse reactions (thrombocytopenia, anemia, neutropenia, and/or pancytopenia) have been reported in patients receiving ZEJULA

    • In PRIMA, the overall incidence of Grade ≥3 thrombocytopenia, anemia, and neutropenia were reported, respectively, in 39%, 31%, and 21% of patients receiving ZEJULA. Discontinuation due to thrombocytopenia, anemia, and neutropenia occurred, respectively, in 4%, 2%, and 2% of patients

    • In patients who were administered a starting dose of ZEJULA based on baseline weight or platelet count, Grade ≥3 thrombocytopenia, anemia, and neutropenia were reported, respectively, in 22%, 23%, and 15% of patients receiving ZEJULA. Discontinuation due to thrombocytopenia, anemia, and neutropenia occurred, respectively, in 3%, 3%, and 2% of patients

    • Do not start ZEJULA until patients have recovered from hematological toxicity caused by prior chemotherapy (≤Grade 1). Monitor complete blood counts weekly for the first month, monthly for the next 11 months, and periodically thereafter

    • If hematological toxicities do not resolve within 28 days following interruption, discontinue ZEJULA, and refer the patient to a hematologist for further investigations


    ZEJULA. Prescribing Information. GlaxoSmithKline; 2021.

    NARRATOR:
    Hematologic adverse reactions, including thrombocytopenia, anemia, neutropenia, and/or pancytopenia, have been reported in patients receiving ZEJULA.

    The overall incidence of Grade 3 or higher thrombocytopenia, anemia, and neutropenia were reported, respectively, in 39%, 31%, and 21% of patients receiving ZEJULA in PRIMA. Discontinuation due to thrombocytopenia, anemia, and neutropenia occurred, respectively, in 4%, 2%, and 2% of patients in PRIMA.

    In patients who were administered a starting dose of ZEJULA based on baseline weight or platelet count in PRIMA, Grade 3 or higher thrombocytopenia, anemia, and neutropenia were reported, respectively, in 22%, 23%, and 15% of patients receiving ZEJULA. Discontinuation due to thrombocytopenia, anemia, and neutropenia occurred, respectively, in 3%, 3%, and 2% of patients.

    Do not start ZEJULA until patients have recovered from hematological toxicity caused by previous chemotherapy by achieving a Grade of 1 or less.

    Monitor complete blood counts weekly for the first month, monthly for the next 11 months of treatment, and periodically thereafter. If hematological toxicities do not resolve within 28 days following interruption, discontinue ZEJULA and refer the patient to a hematologist for further investigations.



    ONSCREEN TEXT:
    Important Safety Information:
    Hematologic adverse reactions

    JOSHUA KESTERSON:
    Additional important safety information will be reviewed later in this presentation.



    ONSCREEN TEXT:
    Despite optimal surgical outcomes and high response rates to first-line platinum-based chemotherapy, the outlook in advanced ovarian cancer remains poor1–3

    [Line graph] Tumor volume vs Disease-free survival (months)
    First-line chemotherapy; Platinum-sensitive relapses; Platinum-resistant relapses
    Surgery; PFI: 12 months*; 8 months*; 4 months*

    >40% of patients fail to respond to subsequent platinum-based chemotherapy, making them ineligible for second-line maintenance treatment with a PARP inhibitor3–5

    * PFIs are estimates for duration of disease control if patients do not receive maintenance therapy. Figure adapted from Giornelli GH. 2016.3

    PARP, poly (ADP-ribose) polymerase; PFI, platinum-free interval or duration of disease control without chemotherapy.

    1. Lorusso D, Mancini M, Di Rocco R, et al. Int J Surg Oncol. 2012;2012:613980. 2. SEER. Cancer Stat Facts: Ovarian Cancer. Bethesda, MD: National Cancer Institute. https://seer.cancer.gov/statfacts/html/ovary.html. [Accessed April 2021].
    3. Giornelli GH. SpringerPlus. 2016;5:1197. 4. Bruchim I, Jarchowsky-Dolberg O, Fishman A. Eur J Obstet Gynecol Reprod Biol. 2013;166(1):94–98. 5. Aghajanian C, Blank SV, Goff BA, et al. J Clin Oncol. 2012;30(17):2039–2045.

    JOSHUA KESTERSON:
    Let’s begin our discussion of the unmet need in ovarian cancer by understanding the prognosis of patients with ovarian cancer.

    Despite optimal surgical outcomes and high response rates to first-line platinum-based chemotherapy, the outlook for patients with advanced ovarian cancer remains poor.
    In addition, the window of opportunity with PARP inhibitor maintenance treatment diminishes with each relapse.

    More than 40% of patients fail to respond to subsequent platinum-based chemotherapy, making them ineligible for second-line maintenance treatment with a PARP inhibitor.


    ONSCREEN TEXT:
    Despite the optimal outcomes of surgery and chemotherapy, the risk of progression in advanced ovarian cancer remains high1,2

    [Graphic] 85% of women with advanced disease experience a relapse after initial treatment1

    • Maintenance treatments are proven to reduce the risk of progression or death3–6
    • When selecting a first-line maintenance therapy it is important to consider:
      • Platinum-responsive patients with or without a specific biomarker may be eligible, but not all PARP inhibitors are indicated for all comers4–6
      • BRCA and HRD testing may help predict potential magnitude of benefit7
      • Patients may have preferences related to route and frequency of treatment administration8


    BRCA, breast cancer susceptibility gene; HRD, homologous recombination deficiency; PARP, poly (ADP-ribose) polymerase.

    1. Lorusso D, Mancini M, Di Rocco R, et al. Int J Surg Oncol. 2012;2012:613980.
    2. Howlader N, Noone AM, Krapcho M, et al., (eds) SEER. Cancer Statistics Review. 1975–2016. Bethesda, MD: National Cancer Institute. https://seer.cancer.gov/csr/1975_2016/, based on November 2018 SEER data submission, posted to the SEER website, April 2019 [Accessed April 2021]. 3. AVASTIN (bevacizumab). Prescribing Information. Genentech, Inc; 2021. 4. ZEJULA (niraparib). Prescribing Information. GlaxoSmithKline; 2021. 5. LYNPARZA (olaparib). Prescribing Information. AstraZeneca Pharmaceuticals LP; 2021. 6. RUBRACA (rucaparib). Prescribing Information. Clovis Oncology, Inc; 2020. 7. Mirza MR, Clomen RL, González-Martín A, et al. Ann Oncol. 2020;31(9):1148–1159. 8. Eek D, Krohe M, Mazar I, et al. Patient Prefer Adherence. 2016;10:1609–1621.

    JOSHUA KESTERSON:
    Furthermore, eighty-five percent of patients with advanced ovarian cancer will experience disease recurrence after initial treatment.

    Maintenance treatments are proven to reduce the risk of progression or death in advanced ovarian cancer.

    When selecting a first-line maintenance therapy, it is important to consider the following points:

    • Platinum-responsive patients with or without a specific biomarker may be eligible, but not all PARP inhibitors are indicated for all patients
    • BRCA and homologous recombination deficiency testing may help predict the potential magnitude of benefit, and
    • Patients may have preferences related to route and frequency of treatment administration



    ONSCREEN TEXT:
    Up to half of advanced ovarian cancers are positive for a biomarker linked to gene repair deficiencies

    Homologous recombination (HR) status is defined as either:

    • HR proficient (HRp): “no deficiency in DNA repair”
    • HR deficient (HRd): “deficient DNA repair”


    [Pie chart] HRp; HRp 50%; HRd; BRCAm 25%; HRd BRCAwt 25%

    HRd can arise from mutations in multiple components of the HR pathway, most commonly BRCA

    Figure adapted from Konstantinopoulos PA, et al. 2015.

    BRCA, breast cancer susceptibility gene; BRCAm, BRCA mutated; BRCAwt, BRCA wild-type; HR, homologous recombination; HRd, homologous recombination deficient/ deficiency; HRp, homologous recombination proficient/proficiency.

    Konstantinopoulos PA, Ceccaldi R, Shapiro GI, et al. Cancer Discov. 2015;5(11):1137–1154.

    JOSHUA KESTERSON:
    Now let’s talk about biomarkers in ovarian cancer. As shown in the pie chart, up to half of advanced ovarian cancers are positive for a biomarker linked to gene repair deficiencies.

    Homologous recombination, or HR, is the cellular process that enables double-strand DNA break repair in healthy cells.

    Tumors with functional HR are referred to as HR proficient, or HRp.

    Tumors with defective HR are referred to as HR deficient, or HRd.

    HRd can arise from mutations in multiple components of the HR pathway, including BRCA1 and 2.

    Other HR pathway alterations reported in ovarian cancer include mutations in Fanconi anemia genes, RAD genes, CDK12, and other HR genes, such as ATM, ATR, CHEK1, and CHEK2.

    ONSCREEN TEXT:
    Real-world data suggest that many eligible women do not currently receive frontline maintenance therapy

    JOSHUA KESTERSON:
    Real-world data suggest that many eligible women do not currently receive frontline maintenance therapy.

    In this data set, maintenance therapy-eligible patients, were defined as in complete or partial response to frontline platinum-based chemotherapy and were required to have received 4 to 9 cycles of platinum-based chemotherapy and started a PARP inhibitor within 90 days from last platinum-based chemotherapy.


    ONSCREEN TEXT:
    Real-world data suggest that many eligible women do not currently receive frontline maintenance therapy

    Many maintenance-eligible* ovarian cancer patients are receiving active surveillance

    [Graphic] Among all eligible patients (N=274) 61% currently receive no maintenance therapy

    [Graphic] 26%
    Among eligible BRCAm patients (N=54)
    [Graphic] 65%
    Among eligible BRCAwt patients(N=182) 65%
    Currently receive no maintenance therapy

    * Based on Flatiron electronic medical record database of patients with ovarian cancer with last platinum administration between February 2020 and January 2021. Maintenance-eligible rules: (1) 4–9 cycles of platinum-based chemotherapy, (2) started PARPi within 90 days from last platinum-based chemotherapy.

    BRCA, breast cancer susceptibility gene; BRCAm, BRCA mutated; BRCAwt, BRCA wild-type; PARPi, poly (ADP-ribose) polymerase inhibitor.

    Data on file, GlaxoSmithKline.

    JOSHUA KESTERSON:
    Despite being eligible, among these patients who received their last platinum administration between February 2020 and January 2021, 61% received no frontline maintenance therapy.

    Among this group, 26% of BRCA-mutated patients and 65% of BRCA wild-type patients received no frontline maintenance therapy.


    ONSCREEN TEXT:
    ZEJULA is the only once-daily PARPi approved for first-line maintenance treatment in platinum-responsive advanced ovarian cancer1–3

    [Table] The only once-daily PARPi indicated for first-line maintenance of advanced ovarian cancer regardless of biomarker status1–3

    HRd; 50% of patients with OC4; BRCAm or BRCAwt;

    HRp; 50% of patients with OC4; BRCAwt
    First-line maintenance (following platinum response);
    [Graphic] Check, Check, Check

    BRCA, breast cancer susceptibility gene; BRCAm, BRCA mutation; BRCAwt, BRCA wild-type; HRd, homologous recombination deficient; HRp, homologous recombination proficient; OC, ovarian cancer; PARPi, poly (ADP-ribose) polymerase inhibitor.

    1. ZEJULA. Prescribing Information. GlaxoSmithKline; 2021. 2. LYNPARZA (olaparib). Prescribing Information. AstraZeneca Pharmaceuticals LP; 2021. 3. RUBRACA (rucaparib). Prescribing Information. Clovis Oncology, Inc; 2020. 4. Konstantinopoulos PA, Ceccaldi R, Shapiro GI, et al. Cancer Discov. 2015;5(11):1137–1154.

    JOSHUA KESTERSON:
    ZEJULA is the only once-daily PARP inhibitor approved for first-line maintenance treatment in platinum-responsive advanced ovarian cancer.

    As a reminder, 50% of high-grade serous ovarian tumors are homologous recombination deficient—they can be either BRCA mutated or BRCA wild-type. The other 50% are homologous recombination proficient. ZEJULA is approved as first-line maintenance following response to platinum regardless of these biomarker statuses.


    ONSCREEN TEXT:
    Important Safety Information:
    Hypertension and hypertensive crisis

    JOSHUA KESTERSON:
    Now, let’s review some additional important safety information.


    ONSCREEN TEXT:
    Important Safety Information:
    Hypertension and hypertensive crisis

    Hypertension and hypertensive crisis have been reported in patients receiving ZEJULA

    • In PRIMA, Grade 3-4 hypertension occurred in 6% of patients receiving ZEJULA vs 1% of patients receiving placebo, with no reported discontinuations
    • Monitor blood pressure and heart rate at least weekly for the first two months, then monthly for the first year, and periodically thereafter during treatment with ZEJULA
    • Closely monitor patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension
    • Manage hypertension with antihypertensive medications and adjustment of the ZEJULA dose, if necessary


    ZEJULA. Prescribing Information. GlaxoSmithKline; 2021.

    NARRATOR:
    Hypertension and hypertensive crisis have been reported in patients receiving ZEJULA.
    Grade 3 or 4 hypertension occurred in 6% of patients receiving ZEJULA versus 1% of patients receiving placebo in PRIMA, with no reported discontinuations.

    Monitor blood pressure and heart rate at least weekly for the first 2 months, then monthly for the first year, and periodically thereafter during treatment.

    Closely monitor patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

    • Manage hypertension with antihypertensive medications and adjust the ZEJULA dose, if necessary



    ONSCREEN TEXT:
    Important Safety Information:
    Posterior reversible encephalopathy syndrome (PRES)

    Posterior reversible encephalopathy syndrome (PRES) occurred in 0.1% of 2,165 patients treated with ZEJULA in clinical trials and has also been described in postmarketing reports

    • Monitor all patients for signs and symptoms of PRES, which include seizure, headache, altered mental status, visual disturbance, or cortical blindness, with or without associated hypertension
    • Diagnosis requires confirmation by brain imaging
    • If suspected, promptly discontinue ZEJULA and administer appropriate treatment
    • The safety of reinitiating ZEJULA is unknown

     

    PRES, posterior reversible encephalopathy syndrome.

    ZEJULA. Prescribing Information. GlaxoSmithKline; 2021.

    NARRATOR:
    Posterior reversible encephalopathy syndrome, or PRES, occurred in 0.1% of two thousand one hundred sixty-five patients treated with ZEJULA in clinical trials. PRES has also been described in postmarketing reports.

    Monitor all patients for signs and symptoms of PRES, which include seizure, headache, altered mental status, visual disturbance, or cortical blindness, with or without associated hypertension

    Diagnosis of PRES requires confirmation by brain imaging. If PRES is suspected, promptly discontinue ZEJULA and administer appropriate treatment. The safety of reinitiating ZEJULA is unknown.


    ONSCREEN TEXT:
    Important Safety Information:
    Embryo-fetal toxicity and lactation, and allergic reactions to FD&C Yellow No. 5

    Based on its mechanism of action, ZEJULA can cause fetal harm

    • Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 6 months after receiving their final dose of ZEJULA
    • Because of the potential for serious adverse reactions from ZEJULA in breastfed infants, advise lactating women to not breastfeed during treatment with ZEJULA and for 1 month after receiving the final dose


    ZEJULA capsules contain FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons

    • Although the overall incidence in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity

     

    ZEJULA. Prescribing Information. GlaxoSmithKline; 2021.

    NARRATOR:
    Based on its mechanism of action, ZEJULA can cause fetal harm.

    Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 6 months after receiving their final dose of ZEJULA.

    Because of the potential for serious adverse reactions in breastfed infants from ZEJULA, advise lactating women not to breastfeed during treatment with ZEJULA and for 1 month after receiving the final dose.

    ZEJULA capsules contain FD&C Yellow No. 5, also known as tartrazine, which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons.

    Although the overall incidence of such reactions in the general population is low, they are frequently seen in patients who also have aspirin hypersensitivity.


    ONSCREEN TEXT:
    Most common ARs and lab abnormalities in first-line maintenance for
    advanced ovarian cancer

    Most common ARs in the PRIMA trial of ZEJULA as first-line maintenance for advanced ovarian cancer

    • Most common adverse reactions (Grades 1–4) in ≥10% of all patients who received ZEJULA in PRIMA were thrombocytopenia (66%), anemia (64%), nausea (57%), fatigue (51%), neutropenia (42%), constipation (40%), musculoskeletal pain (39%), leukopenia (28%), headache (26%), insomnia (25%), vomiting (22%), dyspnea (22%), decreased appetite (19%), dizziness (19%), cough (18%), hypertension (18%), AST/ALT elevation (14%), and acute kidney injury (12%)

     

    [Table] Abnormal laboratory findings in ≥25% of all patients receiving ZEJULA in PRIMA
    Grades 1–4; ZEJULA (N=484); Placebo (n=244); Grades 3–4; ZEJULA (N=484); Placebo (n=244)
    Decreased hemoglobin; 87; 66; 29; 1
    Decreased platelets; 74; 13; 37; 0
    Decreased leukocytes; 71; 36; 9; 0
    Increased glucose; 66; 57; 3; 3
    Decreased neutrophils; 66; 25; 23; 1
    Decreased lymphocytes; 51; 29; 7; 3
    Increased alkaline phosphatase; 46; 21; 1; 0
    Increased creatinine; 40; 23; 0; 0
    Decreased magnesium; 36; 34; 1; 0
    Increased aspartate aminotransferase; 35; 17; 1; 0.4
    Increased alanine aminotransferase; 29; 17; 2; 1

    ALT, alanine aminotransferase; AR, adverse reaction; AST, aspartate aminotransferase.

    ZEJULA. Prescribing Information. GlaxoSmithKline; 2021.

    NARRATOR:
    This slide includes the most common adverse reactions in at least 10% of all patients who received ZEJULA in PRIMA and the most common lab abnormalities in at least 25% of patients who received treatment with ZEJULA.

    The most common adverse reactions including Grades 1 through 4 in at least 10% of all patients who received ZEJULA in PRIMA were:

    • thrombocytopenia (66%)
    • anemia (64%)
    • nausea (57%)
    • fatigue (51%)
    • neutropenia (42%)
    • constipation (40%)
    • musculoskeletal pain (39%)
    • leukopenia (28%)
    • headache (26%)
    • insomnia (25%)
    • vomiting (22%)
    • dyspnea (22%)
    • decreased appetite (19%)
    • dizziness (19%)
    • cough (18%)
    • hypertension (18%)
    • aspartate aminotransferase or alanine aminotransferase elevation (14%)
    • acute kidney injury (12%)


    Common lab abnormalities including Grades 1 through 4 in at least 25% of patients who received treatment with ZEJULA in PRIMA included decreased hemoglobin (87%), decreased platelets (74%), decreased leukocytes (71%), increased glucose (66%), decreased neutrophils (66%), decreased lymphocytes (51%), increased alkaline phosphatase (46%), increased creatinine (40%), decreased magnesium (36%), increased AST (35%), and increased ALT (29%).


    ONSCREEN TEXT:
    Thank you for your attention

    For more information, please visit www.zejulahcp.com

    To report SUSPECTED ADVERSE REACTIONS, contact GSK at 1-888-835-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

    Trademarks are property of their respective owners.
    [GSK logo]
    ©2022 GSK or licensor.
    NRPSTBD220003 January 2022
    Produced in USA.

    JOSHUA KESTERSON:
    Thank you for your attention to this presentation.
    To report suspected adverse reactions, contact GSK or the FDA.
    Please refer to the full prescribing information at zejulahcp.com.
    If you have additional questions, please refer to zejulahcp.com.

ONCE-DAILY ZEJULA

IS APPROVED FOR FIRST-LINE MAINTENANCE IN ADULTS WITH PLATINUM-RESPONSIVE ADVANCED OVARIAN CANCER REGARDLESS OF BIOMARKER STATUS.1

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Reference: 1. ZEJULA (niraparib). Prescribing Information. GlaxoSmithKline; 2021.