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An Overview of the PRIMA Trial Design and Efficacy

Learn about the PRIMA trial design and efficacy from Dr. Joshua Kesterson.

Learn about the PRIMA trial design and efficacy from Dr. Joshua Kesterson.

  • VIDEO TRANSCRIPT | 15:13

    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:
    PRIMA Trial Design & Efficacy

    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 PRIMA Trial Design and Efficacy.

    This presentation will discuss ZEJULA capsules, also known as niraparib, 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:
    PRIMA was an important Phase III trial in advanced ovarian cancer1,2
    The PRIMA trial assessed ZEJULA as a first-line maintenance therapy in patients with advanced ovarian cancer in partial or complete response to platinum-based chemotherapy, regardless of biomarker status1,2

    [Trial Schema] Patients with:

    • Stages III–IV epithelial ovarian, fallopian tube, or primary peritoneal cancer
    • Complete or partial response to first-line platinum-based chemotherapy


    2:1 randomization (N=733)
    ZEJULA* once daily (n=487)
    Placebo once daily (n=246)
    Primary endpoints (assessed by BICR):

    • Median PFS in patients who had HRd tumors
    • Median PFS in the overall population


    Patients were stratified based on neoadjuvant chemotherapy administered (yes or no), best response to 1st platinum therapy (CR or PR) and homologous-recombination (HR) status (deficient [HR-deficient], proficient [HR-proficient], or not determined)

    * Patients in PRIMA received an individualized starting dose of either 200 mg/day or 300 mg/day based on their baseline body weight or platelet count (n=255). PRIMA also included patients who received a fixed starting dose of 300 mg/day, regardless of body weight or platelet count (n=473).

    HR status was determined using Myriad myChoice CDx as tBRCAm and/or GIS ≥42.

    1. González-Martín A, Pothuri B, Vergote I, et al. N Engl J Med. 2019;381(25):2391–2402. 2. ZEJULA. Prescribing Information. GlaxoSmithKline; 2021.

    JOSHUA KESTERSON:
    Now let’s look at the PRIMA trial design.

    PRIMA was a randomized, double-blind, Phase 3, placebo-controlled trial that evaluated the safety and efficacy of ZEJULA in patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer at risk for recurrence after complete or partial response to first-line platinum-based chemotherapy.

     

    Within 12 weeks after completion of the last dose of chemotherapy, patients were randomized 2-to-1 to receive either ZEJULA once daily or placebo once daily for 36 months or until disease progression.

    In the initial protocol, all patients began treatment with a fixed 300-milligram dose. A protocol amendment incorporated an individualized starting dose of 200 or 300 milligrams depending on baseline body weight or platelet count.

    Randomization was stratified by clinical response after first-line platinum-based chemotherapy, receipt of neoadjuvant chemotherapy, and tumor homologous recombination deficiency status, as determined by the Myriad myChoice companion diagnostic test. CT or MRI was performed to assess disease progression every 12 weeks until treatment discontinuation.

    The primary endpoints were progression-free survival in patients who had tumors with homologous recombination deficiency and then in patients in the overall population, as determined on hierarchical testing.

    Progression-free survival was defined as time from randomization to the earliest date of objective disease progression on imaging according to the Response Evaluation Criteria in Solid Tumors, or RECIST, version 1.1, or death from any cause.

    An independent radiological review and a central clinician review conducted in a blinded manner were used to define the date of disease progression.
    Clinical progression was reviewed if an increased cancer antigen-125 level was accompanied by histologic proof or clinical symptoms.


    ONSCREEN TEXT:
    PRIMA enrolled a broad patient population, including patients with poor prognoses1–3

    Of patients in the overall population:

    • 85% had residual disease after primary debulking surgery*3
    • 35% had stage IV disease1,2
    • 67% had received neoadjuvant chemotherapy1,2


    This highlights that the PRIMA trial population included patients at high risk of progression2

    * Stage III and IV disease with visible residual tumor (>0 cm) after primary debulking surgery.

    PFS, progression-free survival.

     

    1. ZEJULA. Prescribing Information. GlaxoSmithKline; 2021. 2. González-Martín A, Pothuri B, Vergote I, et al. N Engl J Med. 2019;381(25):2391–2402. 3. Data on file, GlaxoSmithKline.

    JOSHUA KESTERSON:
    PRIMA included patients with a poor prognosis. 85% of patients had residual disease after primary debulking surgery, 35% had stage IV disease, and 67% had received neoadjuvant chemotherapy. These percentages highlight that the PRIMA trial population included patients at high risk of progression.


    ONSCREEN TEXT:
    Demographic and clinical characteristics at baseline were balanced in the two arms of the trial1,2

    [Table] Characteristic; ZEJULA (n=487); PLACEBO (n=246)
    Age, years
    Median (min,max); 62 (32,85); 62 (33,88)
    ECOG performance status; Percentage of patients; Percentage of patients
    0; 69; 71
    1; 31; 29
    Stage at diagnosis
    III; 65; 64
    IV; 35; 36
    Residual disease after PCS or ICS
    No visible disease; 46; 48
    Visible disease; 45; 46
    No surgery; 3; 1
    Prior neoadjuvant chemotherapy
    Yes; 66; 68
    No; 34; 32
    Best response to platinum therapy
    Complete response; 69; 70
    Partial response; 31; 30

    Table adapted from González-Martín A, et al. 2019.1,2

    ECOG, Eastern Cooperative Oncology Group; ICS, interval cytoreductive surgery; max, maximum; min, minimum; PCS, primary cytoreductive surgery.

    1. González-Martín A, Pothuri B, Vergote I, et al. N Engl J Med. 2019;381(25):2391–2402. 2. González-Martín A, Pothuri B, Vergote I, et al. Niraparib therapy in patients with newly diagnosed advanced ovarian cancer after chemotherapy: PRIMA/ENGOT-OV26/GOG-3012 Study. Presented at ESGO 21st European Congress on Gynaecological Oncology; Athens, Greece, November 2–5, 2019.

    JOSHUA KESTERSON:
    You can see here, the demographic and clinical characteristics of the patients at baseline were balanced in the two trial groups. These characteristics included age, Eastern Cooperative Oncology Group, or ECOG, performance status, stage at diagnosis, residual disease after primary cytoreductive surgery or interval cytoreductive surgery, prior neoadjuvant chemotherapy, and best response to platinum therapy.


    ONSCREEN TEXT:
    In the PRIMA trial, ZEJULA was shown to be effective regardless of biomarker status1,2
    [Arrow graphic]
    Significantly improved median PFS regardless of biomarker status1,2

    [2X graphic]
    Doubled median PFS vs placebo in HRd patients1,2

    [Chart graphic]
    Reduction in risk of progression or death observed in prespecified exploratory analyses of the BRCAm and HRd BRCAwt subgroups*3

    *These prespecified subgroup analyses were exploratory in nature and were not powered to detect a statistically significant treatment effect; therefore, results should be interpreted with caution.

    BRCA, breast cancer susceptibility gene; BRCAm, BRCA mutation; HRd, homologous recombination deficient; PFS, progression-free survival.

    1. ZEJULA. Prescribing Information. GlaxoSmithKline; 2021. 2. González-Martín A, Pothuri B, Vergote I, et al. N Engl J Med. 2019;381(25):2391–2402. 3. Monk BJ, Han S, Pothuri B, et al. Efficacy of niraparib therapy in patients with newly diagnosed advanced ovarian cancer by BRCA and homologous recombination status: PRIMA/ENGOT-OV26/GOG-3012 Study. Oral presentation at the Society of Gynecologic Oncology (SGO) 2020 Webinar Series.

    JOSHUA KESTERSON:
    Since we have discussed the trial design and patient population included in PRIMA, let’s review the efficacy data. In the PRIMA trial, ZEJULA significantly improved median progression-free survival regardless of biomarker status and doubled median progression-free survival versus placebo in homologous recombination deficient patients. A reduction in the risk of progression or death was observed in prespecified exploratory analyses of the BRCA mutation and homologous recombination deficient BRCA wild-type subgroups. Please note that these prespecified subgroup analyses were exploratory in nature and were not powered to detect a statistically significant treatment effect; therefore, results should be interpreted with caution.

    ONSCREEN TEXT:
    ZEJULA significantly improved median PFS in first-line platinum responders, regardless of biomarker status1,2

    [Kaplan-Meier plot] PFS in the overall population (N=733)1,2
    [Y-axis] PFS (%)
    [X-axis] Months
    [Table] Number at risk:
    ZEJULA; 487; 454; 385; 312; 295; 253; 167; 111; 94; 58; 29; 21; 13; 4; 0
    Placebo; 246; 226; 177; 133; 117; 90; 60; 32; 29; 17; 6; 6; 4; 1; 0
    ZEJULA (n=487)*; 13.8 MONTHS MEDIAN PFS
    Placebo (n=246)*; 8.2 MONTHS MEDIAN PFS

    [Graphic] 38% reduction in risk of disease progression or death1,2
    HR: 0.62;
    (95% CI: 0.50–0.76) P<0.0001

    [Graphic] The overall population consisted of:†1
    HRd; BRCAm; BRCAwt
    HRp

    * Censored subjects are indicated by circles.
    Homologous recombination status could not be determined in 111 patients in the PRIMA trial.1

    Figure adapted from González-Martín A, et al. 2019.1

    BRCA, breast cancer susceptibility gene; BRCAm, BRCA mutated; BRCAwt, BRCA wild-type; CI, confidence interval; HR, hazard ratio; HRd, homologous recombination deficient; HRp, homologous recombination proficient; PFS, progression-free survival.

    1. González-Martín A, Pothuri B, Vergote I, et al. N Engl J Med. 2019;381(25):2391–2402. 2. ZEJULA. Prescribing Information. GlaxoSmithKline; 2021.

    JOSHUA KESTERSON:
    This figure shows the Kaplan-Meier plot for progression-free survival in the overall population, where N is seven hundred thirty-three, according to blinded independent central review.

    The median progression-free survival was 13.8 months with ZEJULA versus 8.2 months with placebo, with a hazard ratio of 0.62 (95% confidence interval: 0.50–0.76).

    In other words, ZEJULA was associated with a 38% reduction in risk of disease progression or death compared with placebo in the overall population.

    The overall population consisted of patients with homologous recombination deficient tumors, which included BRCA mutation and BRCA wild-type subgroups, and patients who were homologous recombination proficient. This population also included patients who were considered homologous recombination not determined.


    ONSCREEN TEXT:
    In the HRd population, ZEJULA doubled median PFS compared with placebo1,2

    JOSHUA KESTERSON:
    Of the seven hundred thirty-three patients randomized in PRIMA, 51% had tumors with homologous recombination deficiency. Within this homologous recombination deficient population, 60% had BRCA mutations.


    ONSCREEN TEXT:
    In the HRd population, ZEJULA doubled median PFS compared with placebo1,2

    [Kaplan-Meier plot] PFS in the HRd population (n=373)1,2
    [Y-axis] PFS (%)
    [X-axis] Months
    [Table] Number at risk:
    ZEJULA; 247; 231; 215; 189; 184; 168; 111; 76; 66; 42; 22; 19; 13; 4; 0
    Placebo; 126; 117; 99; 79; 70; 57; 34; 21; 21; 11; 5; 5; 4; 1; 0
    ZEJULA (n=247)*; 21.9 MONTHS MEDIAN PFS
    Placebo (n=126)*; 10.4 MONTHS MEDIAN PFS

    [Graphic] 57% reduction in risk of disease progression or death1,2
    HR: 0.43; (95% CI: 0.31–0.59) P<0.0001

    60% of patients in the HRd population were BRCAm1
    * Censored subjects are indicated by circles.

    Figure adapted from González-Martín A, et al. 2019.1

    BRCA, breast cancer susceptibility gene; BRCAm, BRCA mutated; CI, confidence interval; HR, hazard ratio; HRd, homologous recombination deficient; PFS, progression-free survival.

    1. González-Martín A, Pothuri B, Vergote I, et al. N Engl J Med. 2019;381(25):2391–2402. 2. ZEJULA. Prescribing Information. GlaxoSmithKline; 2021.

    JOSHUA KESTERSON:

    This figure shows the Kaplan-Meier plot for progression-free survival in the homologous recombination deficient population of 373, according to blinded independent central review.

    The median progression-free survival was twice as long with ZEJULA versus placebo (21.9 months versus 10.4 months, with a hazard ratio of 0.43 [95% confidence interval: 0.31–0.59]).

    In other words, ZEJULA was associated with a 57% reduction in risk of disease progression or death compared with placebo in the homologous recombination deficient population.


    ONSCREEN TEXT:
    A 60% reduction in the risk of disease progression or death compared with placebo was observed in a prespecified exploratory analysis of the BRCAm subgroup1,2

    This prespecified subgroup analysis is exploratory in nature and was not powered to detect a statistically significant treatment effect; therefore, results should be interpreted with caution.

    [Kaplan-Meier plot] PFS in the BRCAm population (n=223)1,2
    [Y-axis] PFS (%)
    [X-axis] Months
    [Table] Number at risk: ZEJULA; 152; 148; 140; 127; 125; 113; 77; 55; 48; 29; 15; 14; 10; 4; 0
    Placebo; 71; 65; 57; 44; 41; 34; 21; 14; 14; 7; 2; 2; 2; 1; 0
    ZEJULA (n=152)*; 22.1 MONTHS MEDIAN PFS
    Placebo (n=71)**; 10.9 MONTHS MEDIAN PFS

    [Graphic] 60% reduction in risk of disease progression or death1,2
    HR: 0.40; (95% CI: 0.27–0.62)

    * Censored subjects are indicated by circles.

    Figure adapted from Monk BJ, et al. 2020.1

    BRCA, breast cancer susceptibility gene; BRCAm, BRCA mutation; CI, confidence interval; HR, hazard ratio; PFS, progression-free survival.

    1. Monk BJ, Han S, Pothuri B, et al. Efficacy of niraparib therapy in patients with newly diagnosed advanced ovarian cancer by BRCA and homologous recombination status: PRIMA/ENGOT-OV26/GOG-3012 Study. Oral presentation at the Society of Gynecologic Oncology (SGO) 2020 Webinar Series. 2. González-Martín A, Pothuri B, Vergote I, et al. N Engl J Med. 2019;381(25):2391–2402.

    JOSHUA KESTERSON:
    This figure shows the Kaplan-Meier plot for progression-free survival in the subgroup of two hundred twenty-three patients in PRIMA with BRCA mutations, according to blinded independent central review.

    A 60% reduction in the risk of disease progression or death compared with placebo was observed in a prespecified exploratory analysis of this BRCA mutation subgroup.
    This prespecified subgroup analysis is exploratory in nature and was not powered to detect a statistically significant treatment effect; therefore, results should be interpreted with caution.


    ONSCREEN TEXT:
    A 50% reduction in the risk of disease progression or death compared with placebo was observed in a prespecified exploratory analysis of the HRd BRCAwt subgroup1

    This prespecified subgroup analysis is exploratory in nature and was not powered to detect a statistically significant treatment effect; therefore, results should be interpreted with caution.

    [Kaplan-Meier plot] PFS in the HRd BRCAwt population (n=150)1,2
    [Y-axis] PFS (%)
    [X-axis] Months
    [Table] Number at risk:
    ZEJULA; 95; 83; 75; 62; 59; 55; 34; 21; 18; 13; 7; 5; 3; 0; 0
    Placebo; 55; 52; 42; 35; 29; 23; 13; 7; 7; 4; 3; 3; 2; 0; 0
    ZEJULA (n=95)*; 19.6 MONTHS MEDIAN PFS
    Placebo (n=55)*; 8.2 MONTHS MEDIAN PFS

    [Graphic] 50% reduction in risk of disease progression or death1,2
    HR: 0.50; (95% CI: 0.31–0.83)

    The efficacy with ZEJULA was observed to be consistent in HRd subgroups, regardless of BRCA status1,2

    * Censored subjects are indicated by circles.

    Figure adapted from Monk BJ, et al. 2020.1

    BRCA, breast cancer susceptibility gene; BRCAwt, BRCA wild-type; CI, confidence interval; HR, hazard ratio; HRd, homologous recombination deficient; PFS, progression-free survival.

    1. Monk BJ, Han S, Pothuri B, et al. Efficacy of niraparib therapy in patients with newly diagnosed advanced ovarian cancer by BRCA and homologous recombination status: PRIMA/ENGOT-OV26/GOG-3012 Study. Oral presentation at the Society of Gynecologic Oncology (SGO) 2020 Webinar Series. 2. González-Martín A, Pothuri B, Vergote I, et al. N Engl J Med. 2019;381(25):2391–2402.

    JOSHUA KESTERSON:
    Here we can see the Kaplan-Meier plot for progression-free survival in the subgroup of one hundred fifty patients in PRIMA with homologous recombination deficient BRCA wild-type, according to blinded independent central review.

    A 50% reduction in the risk of disease progression or death compared with placebo was observed in a prespecified exploratory analysis of this homologous recombination deficient BRCA wild-type subgroup.

    This prespecified subgroup analysis is exploratory in nature and was not powered to detect a statistically significant treatment effect; therefore, results should be interpreted with caution.


    ONSCREEN TEXT:
    A reduction in the risk of disease progression or death was observed with ZEJULA compared with placebo across multiple patient subgroups1,2

    These prespecified subgroup analyses were exploratory in nature and were not powered to detect statistically significant treatment effects; therefore, results should be interpreted with caution.

    [Table] Patient subgroup; ZEJULA n/N (%); Placebo n/N (%); HR for disease progression or death (95% CI); Median PFS (months); ZEJULA; Placebo
    All patients;
    232/487 (47.6); 155/246 (63.0); 0.62 (0.50–0.76);13.8; 8.2
    Homologous recombination status
    BRCAm; 49/152 (32.2); 40/71 (56.3); 0.40 (0.27–0.62); 22.1; 10.9
     HRd, BRCAwt; 32/95 (33.7); 33/55 (60.0); 0.50 (0.31–0.83); 19.6; 8.2
     HRp; 111/169 (65.7); 56/80 (70.0); 0.68 (0.49–0.94); 8.1; 5.4
     Not determined; 40/71 (56.3); 26/40 (65.0); 0.85 (0.51–1.43)
    Stage of disease at initial diagnosis
     III; 143/318 (45.0); 103/158 (65.2); 0.54 (0.42–0.70)
     IV; 89/169 (52.7); 52/88 (59.1); 0.79 (0.55–1.12)
    Neoadjuvant chemotherapy
     Yes; 151/322 (46.9); 107/167 (64.1); 0.59 (0.46–0.76)
     No; 81/165 (49.1); 48/79 (60.8); 0.66 (0.46–0.94)
    Best response to platinum therapy
     Complete response; 146/337 (43.3); 100/172 (58.1); 0.60 (0.46–0.77)
     Partial response; 86/150 (57.3); 55/74 (74.3); 0.60 (0.43–0.85)
    [Forest plot]
    0.25; 0.5; 1; 2
    Favors ZEJULA; Favors placebo

    Table adapted from González-Martín A, et al. 2019.1

    BRCA, breast cancer susceptibility gene; BRCAm, BRCA mutation; BRCAwt, BRCA wild-type; CI, confidence interval; HR, hazard ratio; HRd, homologous recombination deficient; HRp, homologous recombination proficient; PFS, progression-free survival.

    1. González-Martín A, Pothuri B, Vergote I, et al. N Engl J Med. 2019;381(25):2391–2402. 2. Supplementary Appendix to: González-Martín A, Pothuri B, Vergote I, et al. N Engl J Med. 2019;381(25):2391–2402.

    JOSHUA KESTERSON:
    Now, let’s look at this table which shows study data on disease progression or death, according to prespecified subgroup analyses.

    These prespecified subgroup analyses were exploratory in nature and were not powered to detect statistically significant treatment effects; therefore, results should be interpreted with caution.

    In multiple patient subgroups with poor prognoses, a reduction in the risk of disease progression was observed with ZEJULA compared to placebo.

    In these prespecified subgroups exploratory analyses, the hazard ratio for progression-free survival was 0.68 in the homologous recombination proficient population and 0.85 in the homologous recombination not determined population.


    ONSCREEN TEXT:
    Overall survival data are not yet mature

    • Overall survival was a key secondary endpoint in PRIMA
    • At the time of PFS analysis, overall survival data were immature with 11% of deaths in the overall population

    PFS, progression-free survival.

    González-Martín A, Pothuri B, Vergote I, et al. N Engl J Med. 2019;381(25):2391–2402.

    JOSHUA KESTERSON:
    Overall survival was a key secondary endpoint in PRIMA.

    At the time of the progression-free survival analysis, overall survival data were immature with 11% of deaths in the overall population.

    Now, let’s review some additional important safety information for ZEJULA.

     


    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
    NRPSTBD220006 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

Learn more about how ZEJULA works and who it may help.

VISIT THE SITE

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