Drug Niraparib Olaparib

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1 Dear NCCN Value Pathway Committee, We are making this submission to provide information that we believe is relevant for developing NCCN Categories of Preference for the use of PARP inhibitors in recurrent ovarian cancer. There are currently two PARP inhibitors approved for 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, namely niraparib (ZEJULA ) and olaparib (Lynparza ). The data sets supporting the approval of these agents were quite distinct. Niraparib approval was supported by the Phase 3 ENGOT-OV16/NOVA trial in which patients with and without germline BRCA mutation were separately evaluated in two independently powered cohorts. 1 Data for olaparib as maintenance treatment in recurrent ovarian cancer patients with a BRCA mutation are available from two trials, the Phase 3 SOLO-2 trial 2,3 and the Phase 2 Study 19 4,5. It is important to note that the data for olaparib in the non-brca mutant population are available only from an exploratory analysis of the Phase 2 Study 19 trial. A comparison of the design of the three trials is provided in Table 1 and Table 2. Table 1: Comparison of trial designs of PARP inhibitors approved for maintenance treatment Drug Niraparib Olaparib Study NOVA 1 Study 19 4,5 SOLO-2 2,3 Phase 3 Yes No (Phase 2) Yes Both BRCA mutant and non- BRCA mutants Mutation status prospectively identified Yes Yes No Yes No Yes Table 2: Data sources for drugs approved for maintenance treatment in ovarian cancer Niraparib 1 Olaparib 2,5 BRCAmut patients Primary endpoint of Phase 3 NOVA trial* Primary endpoint of Phase 3 SOLO-2 trial Non-BRCAmut patients Primary endpoint of Phase 3 NOVA trial* Exploratory analysis of retrospectively identified subgroup in Phase 2 study (Study 19) *Primary endpoint was assessed independently in gbrcamut and non-gbrcamut cohorts Table 3 provides the Progression-free Survival (PFS) results from the trials of PARP inhibitors approved for maintenance treatment. There were a number of differences between the studies in how PFS was assessed which must be considered when evaluating the results of each trial. The niraparib NOVA Trial relied on both imaging and clinical assessment evaluated by blinded, independent central review (BICR)

2 to identify progression. 1 The olaparib trials assessed PFS based solely on imaging, thus excluding clinical progression. 2,5 Radiology scans to detect progression were conducted much more frequently in the NOVA Trial 1 (every 8 weeks through week 56, and every 12 weeks thereafter) compared to both olaparib Study 19 5 (every 12 weeks until week 60, and every 24 weeks thereafter) and olaparib SOLO-2 2 (every 12 weeks until week 72, and every 24 weeks thereafter) trials. Less frequent scanning potentially results in progression being identified later and could lead to longer median PFS. Table 3: PFS for PARP inhibitors approved for maintenance treatment (drug vs placebo in months) Drug Niraparib 1 Median PFS gbrcamut patients 21 vs. 5.5 ( 15.5 mos) Non-gBRCAmut patients 9.3 vs. 3.9 ( 5.4 mos) HR (p-value) 0.27 (p<0.001) 0.45 (p<0.001) BRCA=breast cancer susceptibility gene; gbrcamut= germline BRCA mutated; PFS=progression-free survival; HR=hazard ratio; Mos=months Drug Olaparib 2, 5 Study SOLO-2 Study 19 (Phase 2) Median PFS HR (p-value) Median PFS HR (p-value) BRCAmut 19.1 vs vs patients Non-BRCAmut patients ( 13.6 mos) (p<0.0001) ( 6.9 mos) N/A N/A 7.4 vs. 5.5 ( 1.9 mos) BRCA=breast cancer susceptibility gene; BRCAmut= BRCA mutated; PFS=progression-free survival; HR=hazard ratio; Mos=months (p<0.0001) 0.54 (p=0.0075) In the NOVA trial, in the gbrcamut cohort, median PFS was 21 months in the niraparib-treated group vs. 5.5 months in those receiving placebo, a difference of 15.5 months. 1 For olaparib, the difference in PFS in the BRCAmut population ranged from 6.9 months in Study 19 4,5 to 13.6 months in SOLO-2 2,3. The SOLO-2 trial publication also reported a sensitivity analyses based on BICR. As noted in the olaparib prescribing information, the result of this sensitivity analysis was consistent with the primary endpoint. When appropriate adjustments were made for the censored observations in the BICR, the PFS for this sensitivity analysis was similar in magnitude (14.1 months difference in median vs placebo) to the primary endpoint. 3 In the non-gbrcamut cohort in the NOVA trial, the median PFS was 9.3 months in the niraparib treated group vs 3.9 months in those receiving placebo, a difference of 5.4 months. 1 The olaparib phase 3 SOLO- 2 trial did not include non-brcamut patients. 2 Data for olaparib in the non-brcamut population is available only from Study 19, a Phase 2 trial in which BRCA mutation status was established retrospectively, and randomization was not stratified by BRCA mutation status. 4,5 The analysis of the

3 non-brcamut population was an exploratory subgroup analysis in Study This analysis showed a difference in PFS between olaparib and placebo groups of 1.9 months (Table 3). It should be noted that the populations included in the analysis for the two trials were slightly different. The Study 19 non- BRCAmut population excluded patients with germline and somatic mutation. The non-gbrcamut population from NOVA excluded only patients with germline BRCA mutation. However, patients with somatic mutation constituted only 13.4 of the non-gbrcamut patients in NOVA. While the overall survival (OS) data from the NOVA trial were not yet mature (17 data maturity 9 ), the hazard ratio (HR) for OS at the time of primary PFS analysis was 0.73 (95 CI, to 1.125; p=0.15) in the pooled population, mainly driven by the events in non-gbrcamut cohort. 6 Median had not been reached at the time of analysis. OS data from SOLO-2 are not yet mature at the time of publication. In Study 19, the median OS was 29.8 months in the olaparib group vs 27.8 months in the placebo group in the overall population. 7 In the non-brcamut patients in Study 19, the median overall survival was 24.5 months in the olaparib treated patients compared to 26.6 months in the placebo group 7. The most common Grade 3/4 adverse events (AE) associated with niraparib were hematologic in nature (more detail regarding AE rates is provided in the appendix). These AEs were managed in the NOVA trial through dose modification. 1 The proportion of patients receiving 100mg, 200mg and 300mg at each month is shown in Figure 1. 8 Dose adjustments resulted in a substantial reduction in the incidence of these AEs. The rate of AEs after cycle 3 was relatively low (see Appendix Table A2). Efficacy in patients who required a dose reduction was similar to that in patients who continued treatment at the starting dose of 300mg once daily. 8 The most common Grade 3/4 adverse events reported for olaparib was anemia. 9 The proportion of patients who discontinued treatment due to adverse events was 14.7 in NOVA 1 and 11 in SOLO-2) 2.

4 Figure 1: Proportion of patients receiving niraparib 100mg, 200mg, and 300mg by month in the NOVA trial 8 To assist in the value assessment, we provide below the costs of the two agents. The costs were estimated based on Wholesale Acquisition Cost (WAC) of each drug. The cost of ZEJULA is proportional to the dose administered, with the cost being 2/3 or 1/3 that of the starting dose, depending on the dose administered. Since all olaparib tablet strengths are priced the same, dose reduction does not result in a lower cost for olaparib (Table 4). 11 Based on WAC, the monthly cost of olaparib is 31 higher than the monthly cost of ZEJULA at the most commonly administered dose in the NOVA trial of 200 mg (Figure 2).

5 Table 4: Dose modification options and associated cost for olaparib and ZEJULA 11 Drug Olaparib Niraparib Starting Dose First Dose Reduction Dose 30D Price Notes Dose 30D Price Notes 300mg BID (two 300m QD (three $13, ct 150mg 150mg tabs) 100mg caps) $15,930 90ct 100mg 250mg BID (one Patient shipped 200mg QD (two 100mg tab and $13, ct 150mg and 100mg caps) one 150mg tab) 60ct 100mg $10,620 60ct 100mg 200mg BID (two 100mg QD (one $13, ct 100mg 100mg tabs) 100mg cap) $5,310 30ct 100mg Second Dose Reduction BID=twice daily; tabs=tablet; ct=count; QD=once daily; caps=capsules Figure 2: Comparison of monthly prices based on WAC for olaparib and ZEJULA 1,11 *olaparib price is the same regardless of dose, as price is the same regardless of tablet strength. We hope this information is useful for the committee in developing categories of preference for maintenance treatment in recurrent ovarian cancer.

6 Citations: 1. Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375: Pujade-Lauraine E, Ledermann JA, Selle F, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncology. 2017;18(9): Pujade-Lauraine E, Ledermann JA, Selle F, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(9): Supplementary Appendix 4. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366(15): Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in patients with platinumsensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 2014;15(8): Mirza MR, Monk BJ, Oza AM, et al. ENGOT-OV16/NOVA Trial Niraparib Maintenance Therapy in Patients with Recurrent Ovarian Cancer. Clinical trial presented at: European Society of Medical Oncology 2016 Annual Conference; October 7-11, 2016; Copenhagen, Denmark. 7. Ledermann JA, Harter P, Gourley C, et al. Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis from a randomized, placebo-controlled, double-blind, phase 2 trial. Lancet Oncol. 2016;17: Wang J, Zhang ZY, Mirza MR, et al. The Exposure-Response of Niraparib in Patients with gbrcamut and non-gbrcamut: Results from ENGOT-OV16/NOVA Trial. Presented at European Society of Medical Oncology 2017; September 8-12, 2017; Madrid, Spain. Poster# 933PD. 9. ZEJULA (niraparib) [prescribing information]. Waltham, MA: TESARO, Inc; Lynparza (olaparib) [prescribing information]. Wilmington, DE: AstraZeneca; Truven. RED BOOK Online. Greenwood Village, CO: Truven Health Analytics; 2018.

7 Appendix Table A1: Adverse reactions reported in 10 of patients treated with niraparib Adverse Reaction Niraparib n=367 Grades 1 4* Grades 3 4* Niraparib n=179 n=367 n=179 Nausea Thrombocytopenia Fatigue/Asthenia Anemia Constipation Vomiting Abdominal pain/distention Neutropenia Insomnia Headache Decreased appetite Nasopharyngitis Rash Mucositis/stomatitis Diarrhea Dyspnea Hypertension Myalgia Dyspepsia

8 Adverse Reaction Niraparib n=367 Grades 1 4* Grades 3 4* n=179 Niraparib n=367 n=179 Dizziness Leukopenia Cough Urinary tract infection Arthralgia Anxiety Palpitations Dry mouth AST/ALT elevation Dysgeusia ALT = alanine aminotransferase; AST = aspartate aminotransferase; *CTCAE = Common Terminology Criteria for Adverse Events version Reference: ZEJULA (niraparib) [prescribing information]. Waltham MA: TESARO, Inc.; Table A2: Grade 3/4 adverse events after Cycle 3 with niraparib in the NOVA Trial Adverse events n () Grade 3/4 adverse events that occurred after cycle 3 (n=296) Thrombocytopenia 7 (2.4) Anemia 50 (16.9) Neutropenia 8 (2.7) Fatigue β 9 (3.0) Hypertension - Thrombocytopenia=thrombocytopenia and decreased platelet count. No grade 3 or 4 bleeding events were associated with thrombocytopenia; Anemia=anemia and decreased hemoglobin counts; Neutropenia=neutropenia, decreased neutrophil count, and febrile neutropenia; β Fatigue=fatigue, asthenia, malaise, and lethargy. Reference: Mirza MR, Monk BJ, Oza AM, et al. ENGOT-OV16/NOVA Trial Niraparib Maintenance Therapy in Patients with Recurrent Ovarian Cancer. Clinical trial presented at: ESMO 2016; October 7-11, 2016; Copenhagen, Denmark.

9 Table A3: Adverse events reported in 10 of patients in either treatment group in SOLO-2 Adverse Reaction Olaparib n=195 Grades 1 2* Grades 3 4* Olaparib n=99 n=195 n=99 Nausea Fatigue/asthenia Vomiting Diarrhea Dysgeusia Headache Anemia Abdominal pain Decreased appetite Constipation Cough Arthralgia Neutropenia Hypomagnesemia Pyrexia Dizziness Thrombocytopenia Blood creatinine increased Dyspnea Back pain Dyspepsia

10 Grade 1 2* Grade 3 4* Adverse Reaction Olaparib n=195 n=99 Olaparib n=195 n=99 Upper abdominal pain Nasopharyngitis Urinary tract infection Leukopenia Anemia includes patients with anemia, hemoglobin decreased, hematocrit decreased, and red blood cell count decreased; Neutropenia includes patients with neutropenia, febrile neutropenia, neutropenic sepsis, neutrophil count decreased, granulocytopenia, and granulocyte count decreased; Thrombocytopenia includes patients with thrombocytopenia, and platelet count decreased. The only grade 5 adverse event to occur was in the olaparib group, one patient in the olaparib group had a treatment-emergent adverse event of acute myeloid leukemia with an outcome of death. *CTCAE = Common Terminology Criteria for Adverse Events version 4.0. Reference: Pujade-Lauraine E, Ledermann JA, Selle F, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT- Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncology. 2017;18(9):