Ovarian Cancer: Implications for the Pharmacist

Ovarian Cancer: Implications for the Pharmacist Megan May, Pharm.D., BCOP Objectives Describe the etiology and pathophysiology of ovarian cancer Outline the efficacy and safety of treatment options for ovarian cancer Explain the mechanism of action of poly ADP ribose polymerase inhibitors (PARP inhibitors) available for ovarian cancer Explain how to evaluate the appropriate selection of therapy for specific ovarian cancer patients 1

Epidemiology 5 th most frequent cause of death in women Incidence in 2018 New cases: 22,240 Deaths: 14,070 Primarily post-menopausal disease Median age at diagnosis: 65-69 69 years old Caucasians > African American National Cancer Institute. 2018. Etiology/Pathogenesis Sporadic ovarian cancer etiology unknown Most common type (85-90%) Familial and hereditary syndromes Less common type (10-15%) Incessant ovulation theory Risk of developing ovarian cancer is related to number of ovulatory cycles Tumor suppressor genes BRCA1, BRCA2, p53 National Cancer Institute. 2018. 2

Pathology Epithelial adenocarcinoma Serous Mucinous Endometroid Clear-cell Germ-cell tumor Sex-cord stromal Metastatic from other malignancies Risk Factors Early menarche, late menopause and nulliparity Increased age Prolonged use of ovulatory stimulating drugs Environmental and dietary factors Residence in North American or Northern Europe Caucasian race Genetic factors Hormone replacement therapy 3

Hereditary Risk Family History of Ovarian Cancer Lifetime Risk None 1.4 1.8% 1 first degree relative 3 5% 2 first-degree relatives 7 9% Lynch Syndrome 6 10% Known BRCA 1 and/or BRCA 2 10 80% germline mutation Ovarian Cancer Research Fund Alliance: Risk Factors. https://ocrfa.org/patients/about-ovarian-cancer/risk-factors/ Favorable Factors Multiple pregnancies Breastfeeding Use of prolonged oral contraceptives Tubal ligation Prophylactic oophorectomy 4

Screening No effective screening test for ovarian cancer Low/standard risk (not familial or hereditary) Annual physical and pelvic examination High risk (hereditary ovarian cancer, BRCA 1 or BRCA 2 positive) Pelvic examination, transvaginal ultrasound and CA 125 every 6 12 months starting at age 25 35 Gynecol Oncol 2007; 104:S14. Abstract 10 Prevention Oral contraceptives Use for five or more years decreases risk of ovarian cancer by 50% or more Longer the use, greater the protection Protection can continue for up to 30 years after stopping use Prophylactic oophorectomy Decreases risk of ovarian cancer in high risk patients 5

Signs and Symptoms Bloating Pelvic or abdominal pain Eating satiety Urinary symptoms (frequency or urgency) GI symptoms Pulmonary symptoms Unilateral or bilateral, solid, cystic and/or complex pelvic or adnexal masses CA-125 highly elevated Staging International Federation of Gynecologic Oncologists (FIGO) and AJCC staging systems stems (stages I-IV) IV) Grade 1: well differentiated 2: moderately differentiated 3: poorly differentiated AJCC Cancer Staging Manual, Sixth Edition (2002) 6

FIGO Staging Stage I Growth limited to the ovaries Stage II Growth involving one or both ovaries with pelvic extension Stage III Tumor involving one or more ovaries with tumor outside the pelvis and/or positive retroperitoneal or inguinal lymph nodes Superficial liver metastases Tumor limited to pelvis but malignant extension to small bowel or omentum Stage IV Growth involving one or more ovaries with distant metastases Parenchymal liver metastases Pleural effusion must have positive cytology AJCC Cancer Staging Manual, Sixth Edition (2002) Prognosis Stage of disease Volume of residual disease at time of surgery Histologic subtype and grade CA-125 Stage of Disease % of Cases 5-year Survival I 23 90% II 13 70% III 47 39 59% IV 16 17% Principles and Practice of Gyn Oncol: 3 rd Ed. 7

Primary Treatment (Stages I-II) Comprehensive surgical staging Optimal: < 1 cm residual disease Suboptimal: > 1 cm residual disease Adjuvant combination chemotherapy Taxane + platinum Number of cycles (3 or 6) varies by stage Observation in stage 1A or 1B PDQ Adult Treatment Editorial Board. PDQ Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated 07/19/2018. Available at: https://www.cancer.gov/types/ovarian/patient/ovarian-epithelial-treatment-pdq. Accessed 09/04/2018. GOG-157 Early stage ovarian cancer, high-risk features (n = 457) Randomized following surgery to 3 vs. 6 cycles of paclitaxel + carboplatin Recurrence rate 33% lower in patients treated with 6 cycles (HR: 0.627, not statistically significant) Grade 2 neurotoxicity in 2% vs. 11% patients Bell J, et al. Gynceol Oncol. 2006;102(3):432-439. 8

ICON-1 Trial Early stage, high-grade, or surgically unstaged tumors (n = 477) Randomized, prospective, multi-center Randomized following surgery to 6 cycles of platinum-based chemotherapy vs. observation 5-year survival Progression-free survival (PFS) Platinum x 6 79% 73% Observation 70% 62% Trimbos JB, et al. J Natl Cancer Inst. 2003;95(2):105-112. ACTION Trial Randomized, prospective, multi center trial, early stage high grade tumors only (n = 448) Stage IA or IB well differentiated tumors excluded Following surgery, patients randomized to receive 4 cycles of platinum based chemotherapy vs. observation Included grade 2 3 tumors only At median follow up 5.5 years, no statistical difference in overall survival (OS) or PFS Statistically significant survival benefit only seen in sub group analysis of patients who did not undergo optimal surgical staging Trimbos JB, et al. J Natl Cancer Inst. 2003;95(2):105-112. 9

Advance Stage (Stages III-IV) Comprehensive surgical staging Six cycles of adjuvant combination chemotherapy with taxane + platinum or liposomal doxorubicin + carboplatin Intraperitoneal chemotherapy may be an option in stage II or III Occasionally, neoadjuvant chemotherapy PDQ Adult Treatment Editorial Board. PDQ Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated 07/19/2018. Available at: https://www.cancer.gov/types/ovarian/patient/ovarian-epithelial-treatment-pdq. Accessed 09/04/2018. Adjuvant Chemotherapy GOG-111 Paclitaxel + cisplatin improves median survival compared to cyclophosphamide + cisplatin GOG-158 Paclitaxel + carboplatin preferred over paclitaxel + cisplatin due to equal efficacy and reduced toxicity SCOTROC trial Docetaxel is equally efficacious and less neurotoxic than paclitaxel when given in combination with carboplatin Muggia F, et al. JCO. 2000;18(1):106-115. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(6):735-740. Vasey PA, et al. J Natl Cancer Inst. 2004;96:1682-1691. 10

Cisplatin versus Carboplatin Neurotoxicity Nephrotoxicity N/V Cisplatin +++ *paclitaxel 24h infusion Carboplatin + *paclitaxel 3h infusion +++ +++ + ++ In patients with optimally resected stage III ovarian cancer Complete remission and overall survival not different between cisplatin/paclitaxel and carboplatin/paclitaxel Carboplatin regimen easier to administer Ozols RF JCO 2003;21:3194-3200; GOG 158 Paclitaxel versus Docetaxel Neurotoxicity Greater grade 2 & 3 neuropathy with paclitaxel l Neutropenia Greater grade 4 neutropenia with docetaxel Edema Greater with docetaxel 11

IP Therapy Patient selection Stage IIIC (optimal surgical cytoreduction) Good performance status No history of prior bowel surgery or bowel surgery at the time of primary therapy Benefits Substantial improvement in overall survival Risks Infection Leukopenia Dehydration, electrolyte abnormalities Catheter malfunction Abdominal pain Armstrong DK, et al. N Engl J Med. 2006;354:34-43. GOG-172 Stage IIIC ovarian and primary peritoneal cancer and optimal surgical cytoreduction ction were randomized to one of the following (n = 429): IV regimen Paclitaxel 135 mg/m 2 IV over 24 hours on Day 1 + cisplatin 75 mg/m 2 IV on Day 2 every 3 weeks IP regimen Paclitaxel 135 mg/m 2 IV over 24 hours on Day 1 + cisplatin 100 mg/m 2 IP on day 2 + paclitaxel 60 mg/m 2 IP on day 8 every 3 weeks Armstrong DK, et al. N Engl J Med. 2006;354:34-43. 12

GOG-172 Median PFS and OS at five years significantly improved for patients on IP treatment arm (18.3 vs. 23.8 months and 49.7 vs 65.6 months, respectively) Grade 3 and 4 toxicities were significantly worse in patients treated with IP therapy Only 42% of patients randomized to IP therapy completed six cycles of treatment (median=3) Patients unable to tolerate IP therapy were switched to the IV treatment arm QOL was significantly worse for patients in the IP arm while on treatment At 12 months, there was no difference in QOL between the two groups Armstrong DK, et al. N Engl J Med. 2006;354:34-43. Bevacizumab FDA-approved in combination with liposomal doxorubicin, paclitaxel, or topotecan OCEANS Trial AURELIA Trial Bevacizumab in combination with paclitaxel + carboplatin GOG-0213 Bevacizumab monotherapy GOG-0170D CCC-PHII-45 PDQ Adult Treatment Editorial Board. PDQ Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated 07/19/2018. Available at: https://www.cancer.gov/types/ovarian/patient/ovarian-epithelial-treatment-pdq. Accessed 09/04/2018. 13

GOG-218 Phase III randomized, double blind trial Patients with stage III or IV, any gross residual disease (n = 1873) Following surgery, patients were randomized standard chemotherapy (paclitaxel + carboplatin) cycles 1 6 and either Placebo (cycle 2 5) followed by placebo every 3 weeks for 15 months Bevacizumab 15 mg/kg (cycle 2 5) followed by placebo every 3 weeks for 15 months Bevacizumab 15 mg/kg (cycle 2 5) followed by bevacizumab 15 mg/kg every 3 weeks for 15 months Burger RA, et al. J Clin Oncol. 2010;28:18S GOG-218 Statistically significant increase in PFS for patients treated on the chemotherapy + bevacizumab + bevacizumab maintenance (14.1 months) vs. chemotherapy + bevacizumab + placebo maintenance (11.2 months) vs. chemotherapy alone (10.3 months) (HR=0.72) Preliminary OS data shows no difference between groups No difference in QOL detected between any of the three groups Burger RA, et al. J Clin Oncol. 2010;28:18S 14

ICON-7 Phase III, randomized, open label Patients with stage I IV, optimal or suboptimal disease (n=1528) Following surgery, patients were randomized Standard chemotherapy Chemotherapy + bevacizumab 7.5 mg/kg every 3 weeks followed by bevacizumab 7.5 mg/kg maintenance every 3 weeks for 12 cycle (total one year of bevacizumab) Perren TJ, et al. N Engl J Med. 2011;365:2484-2496. ICON-7 At 42 months, the median PFS was modestly improved in the treatment arm vs. the control arm (24.1 months vs. 22.4 months, HR=0.81) Effect of bevacizumab was greater in patients at high risk for progression (PFS 18 months vs. 14.5 months) Median OS was improved in the high risk patient population (36 months vs. 28 months) Toxicity was greater in the bevacizumab treated patients Perren TJ, et al. N Engl J Med. 2011;365:2484-2496. 15

Recurrent, Refractory, and Resistant Ovarian Cancer 60 80% of ovarian cancer patients Length of subsequent remissions is shorter than the initial remission Goal of treatment Improve/eliminate symptoms Achieve an objective response Improve quality of life Delay time to symptomatic disease Prolong survival if possible PDQ Adult Treatment Editorial Board. PDQ Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated 07/19/2018. Available at: https://www.cancer.gov/types/ovarian/patient/ovarian-epithelial-treatment-pdq. Accessed 09/04/2018. Definitions Platinum sensitive disease Initial response to platinum Duration of initial remission > 6 months Longer the initial remission, the greater the likelihood of responding to second and third line agents Probability of response to chemotherapy is 30% or more Platinum resistant disease Initial response to platinum Duration of initial remission < 6 months Probability bilit of response to additional treatment t t is 10 15% 15% Primary progressive (platinum refractory) disease No response and/or progression of disease during primary therapy with platinum Worst prognosis Probability of response to additional chemotherapy <10% PDQ Adult Treatment Editorial Board. PDQ Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated 07/19/2018. Available at: https://www.cancer.gov/types/ovarian/patient/ovarian-epithelial-treatment-pdq. Accessed 09/04/2018. 16

Recurrent Ovarian Cancer Platinum-containing chemotherapy regimens Bevacizumab Chemotherapy and/or bevacizumab PARP inhibitors Clinical trial Cytoreductive surgery PDQ Adult Treatment Editorial Board. PDQ Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated 07/19/2018. Available at: https://www.cancer.gov/types/ovarian/patient/ovarian-epithelial-treatment-pdq. Accessed 09/04/2018. Recurrent Ovarian Cancer Platinum Sensitive Cisplatin/Carboplatin + paclitaxel Carboplatin + liposomal doxorubicin Carboplatin + gemcitabine +/- bevacizumab Cisplatin + gemcitabine Carboplatin + albumin-bound paclitaxel Carboplatin + docetaxel Carboplatin Cisplatin Can consider abdominal radiotherapy Resistant Docetaxel Liposomal doxorubicin Gemcitabine + docetaxel Etoposide (oral) Topotecan Dose-dense paclitaxel Addition of bevacizumab PDQ Adult Treatment Editorial Board. PDQ Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated 07/19/2018. Available at: https://www.cancer.gov/types/ovarian/patient/ovarian-epithelial-treatment-pdq. Accessed 09/04/2018. 17

PARP Inhibitors Poly ADP-ribose polymerase inhibitor DNA repair mechanism BRCA mutated cells more dependent on this mechanism Directly inhibits PARP 1, 2, 3 and increases formation of PARP-DNA complexes, preventing DNA repair cell death FDA- approved PARP inhibitors Rucaparib (Rubraca ) Olaparib (Lynparza ) Niraparib (Zejula ) PDQ Adult Treatment Editorial Board. PDQ Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated 07/19/2018. Available at: https://www.cancer.gov/types/ovarian/patient/ovarian-epithelial-treatment-pdq. Accessed 09/04/2018. FDA-Approved Ovarian Cancer Indications Rucaparib Treatment of advanced ovarian cancer with gbrca or sbrca 2 prior lines of chemotherapy Maintenance treatment of recurrent ovarian cancer in complete or partial response to platinum-based chemotherapy Olaparib Treatment of advanced ovarian cancer with gbrca 3 prior lines of chemotherapy Maintenance treatment of recurrent ovarian cancer in complete or partial response to platinum-based chemotherapy Niraparib Maintenance treatment of recurrent ovarian cancer in complete or partial response to platinum-based chemotherapy Rubraca [prescribing information]. Clovis Oncology. 2017. Lynparza [prescribing information]. AstraZenca. 2018. Zejula [prescribing information]. Tesaro. 2018. 18

FDA-Approved Dosing Rucaparib 600 mg by mouth twice daily Tablet available: 200 mg, 250 mg, 300 mg Olaparib 400 mg capsule by mouth twice daily Capsule available: 50 mg 300 mg tablet by mouth twice daily Tablet available: 100 mg and 150 mg Niraparib 300 mg by mouth once daily Capsule available: 100 mg Rubraca [prescribing information]. Clovis Oncology. 2017. Lynparza [prescribing information]. AstraZenca. 2018. Zejula [prescribing information]. Tesaro. 2018. Treatment versus Maintenance Therapy Treatment An initial iiil treatment used in attempt to shrink hik the current tumor Maintenance therapy Continuing to treat after completion of standard round of chemotherapy Used to avoid or slow the cancer s return Slow the growth of advanced cancer after the initial treatment 19

Risk/Benefits of Maintenance Therapy Benefits May help keep cancer from coming back May slow down cancer growth Disadvantages Side effects Treatment cost More doctor visits Limited information on long term side effects and benefits for each individual PARP Inhibitor Side Effects All have a similar side effects, but some are more common and/or more severe ere in one versus s another Acute myeloid leukemia/myelodysplastic syndrome has been reported in 0.5%-2% of patients Thompson LA. Oncology Nurse Advisor. 2017. 20

ARIEL2: Rucaparib Outcome BRCA Mutation n = 40 BRCA Wild-Type and LOH High n = 82 BRCA Wild-Type and LOH Low n = 70 ORR, % 80 29 10 PFS, months p value (vs LOH-low) 12.8 <0.0001 5.7 0.011 5.2 - Duration of response, months p value (vs LOH-low) 9.2 0.013013 10.8 0.022022 5.6 - LOH = loss of heterozygosity ORR = objective response rate Swisher EM, et al. Lancet Oncol 2017;18:75-87. ARIEL3: Rucaparib Outcome BRCA Mutation Overall Study Population Rucaparib Placebo Rucaparib Placebo n = 130 n = 66 n = 375 n = 189 Median PFS, months 16.6 5.4 13.6 5.4 Coleman RL, et al. Lancet 2017;390(10106):1949-1961. 21

Rucaparib Adverse Effects in 20% of Patients Adverse Effects All Grades (%) n = 377 Grades 3/4 (%) n = 377 Nausea 77 5 Vomiting 46 4 Constipation 40 2 Diarrhea 34 2 Abdominal Pain 32 3 Asthenia/Fatigue 77 11 Anemia 44 25 Thrombocytopenia 21 5 Dysgeusia 39 0.3 Decreased appetite 39 3 Dyspnea 21 0.5 Swisher EM, et al. Lancet Oncol 2017;18:75-87. Rubraca [prescribing information]. Clovis Oncology. 2017. Rucaparib Laboratory Abnormalities in 35% of Patients Laboratory Parameter All Grades (%) n = 377 Grades 3/4 (%) n = 377 Increase in creatinine 92 1 Increase in ALT 74 13 Increase in AST 73 5 Increase in cholesterol 40 2 Decrease in hemoglobin 67 23 Decrease in lymphocytes 45 7 Decrease in platelets 39 6 Decrease in absolute neutrophil count 35 10 Swisher EM, et al. Lancet Oncol 2017;18:75-87. Rubraca [prescribing information]. Clovis Oncology. 2017. 22

SOLO-2: Olaparib Outcome Olaparib n = 196 Placebo n = 99 PFS, months 19.1 5.5 Grade 3 or 4 adverse effects 18% 8% Pujade-Lauraine E, et al. Lancet Oncol. 2017;18(9):1274-1284. Olaparib Adverse Effects in 20% of Patients Adverse Effects All Grades (%) Grades 3/4 (%) Olaparib n = 195 Placebo n = 99 Olaparib n = 195 Placebo n = 99 Anemia 44 9 20 2 Nausea 76 33 3 0 Vomiting 37 19 3 1 Diarrhea 33 22 2 0 Stomatitis 20 16 1 0 Nasopharyngitis/upper respiratory infection/sinusitis/rhinitis/influenza 36 29 0 2 Fatigue 66 39 4 2 Decrease appetite 22 11 0 0 Arthralgia/myalgia 30 28 0 0 Dysgeusia 27 7 0 0 Headache 26 14 1 0 Pujade-Lauraine E, et al. Lancet Oncol. 2017;18(9):1274-1284. Lynparza [prescribing information]. AstraZenca. 2018. 23

Olaparib Laboratory Abnormalities in 25% of Patients Laboratory Parameter All Grades (%) Grades 3/4 (%) Olaparib Placebo Olaparib Placebo n = 195 n = 99 n = 195 n = 99 Increase in mean corpuscular 89 52 - - volume Decrease in hemoglobin 83 69 17 0 Decrease in leukocytes 69 48 5 1 Decrease in lymphocytes 67 37 11 1 Decrease in absolute neutrophil 51 34 7 3 count Increase in serum creatinine 44 29 0 0 Increase in platelets 42 22 2 1 Pujade-Lauraine E, et al. Lancet Oncol. 2017;18(9):1274-1284. Lynparza [prescribing information]. AstraZenca. 2018. NOVA: Niraparib Outcome BRCA Mutation BRCA Wild-Type Niraparib Placebo Niraparib Placebo n = 138 n = 65 n = 234 n = 116 Median PFS, months 21 5.5 12.9 3.8 Mirza MR, et al. N Engl J Med. 2016;375:2154-2164. 24

Niraparib Adverse Effects in 20% of Patients Adverse Effects All Grades (%) Grades 3/4 (%) Niraparib n = 367 Placebo n = 179 Niraparib n = 367 Placebo n = 179 Thrombocytopenia 61 5 29 0.6 Anemia 50 7 25 0 Neutropenia 30 6 20 2 Nausea 74 35 3 1 Constipation 40 20 0.8 2 Vomiting 34 16 2 0.6 Abdominal pain/distention 33 39 2 2 Mucositis/stomatitis 20 6 0.5 0 Diarrhea 20 21 0.3 1 Fatigue/asthenia 57 41 8 0.6 Mirza MR, et al. N Engl J Med. 2016;375:2154-2164. Zejula [prescribing information]. Tesaro. 2018. Niraparib Adverse Effects in 20% of Patients Adverse Effects All Grades (%) Grades 3/4 (%) Niraparib Placebo Niraparib Placebo n = 367 n = 179 n = 367 n = 179 Decreased appetite 25 15 0.3 0.6 Headache 26 11 0.3 0 Nasopharyngitis 23 14 0 0 Dyspnea 20 8 1 1 Rash 21 9 0.5 0 Hypertension 20 5 9 2 Mirza MR, et al. N Engl J Med. 2016;375:2154-2164. Zejula [prescribing information]. Tesaro. 2018. 25

Niraparib Laboratory Abnormalities in 25% of Patients Laboratory Parameter All Grades (%) Grades 3/4 (%) Niraparib Placebo Niraparib Placebo n = 367 n = 179 n = 367 n = 179 Decrease in hemoglobin 85 56 25 0.5 Decrease in platelet count 72 21 35 0.5 Decrease in WBC count 66 37 7 0.7 Decrease in absolute neutrophil 53 25 21 2 count Increase in AST 36 23 1 0 Increase in ALT 28 15 1 2 Mirza MR, et al. N Engl J Med. 2016;375:2154-2164. Zejula [prescribing information]. Tesaro. 2018. Summary Clinical staging is important in determining the appropriate treatment New advances for patients with ovarian cancer with the PARP inhibitors Olaparib and rucaparib is approved in treatment and maintenance Niraparibib is approved in maintenance Treatment should always be individualized 26

Ovarian Cancer: Implications for the Pharmacist Megan May, Pharm.D., BCOP 27