https://openworks.mdanderson.org/sumexp22/1095/thumbnail.jp

Fleming, Nicole

Meyer, Larissa A.

Michael, Victoria

Onstad-Grinsfelder, Michaela

Westin, Shannon N.

Yuan, Yin

English

OpenWorks @ MD Anderson

NOW Feasibility Study of Neoadjuvant Olaparib for Frontline BRCA Mutant Ovarian CancerVictoria Michael1, Shannon N. Westin2, Michaela Onstad Grinsfelder2, Larissa Meyer3, Nicole Fleming3, Ying Yuan4Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center1McGovern Medical School, The University of Texas Health Science Center at Houston1Background• Studies suggest primary ovarian cancer is a chemo-sensitive disease with measurable response in up to 70% of patients [1]• Response to NACT is rare (4-6%) [1]• Recurrence after clinical complete response is ~75% likely [1]• The data suggests the need for better frontline therapy• The standard of care treatment for platinum sensitive ovarian cancer is a platinum-based doublet with or without bevacizumab [2]• For breast cancer, chemotherapy has been replaced in the BRCA mutant population with PARP Inhibition with impressive response rates[3]• Majority of high grade serous ovarian cancers are BRCAwildtype, while 20% have somatic or germline BRCAmutations[4]• Approximately 50% of the tumors evaluated had homologous recombination (HR) repair deficiencies [4]• Olaparib is a potent Polyadenosine 5’diphosphoribose PARP inhibitor. PARP enzymes are involved in repairing DNA SSBs. Inhibition allows SSBs to progress to more serious DSBs [5]• Tumors with HR deficiencies such as BRCA 1/2, RAD51 C/D, and PALB2, cannot repair the DNA damage causing cell apoptosis. • Olaparib may offer efficacious and less toxic cancer treatment compared to available chemotherapy treatment regimens• This is a single-arm, open-label, pilot study to assess the impact of olaparib in women with advanced stage, metastatic BRCA mutant ovarian cancer undergoing neoadjuvant chemotherapy. Patients who are to proceed with NACT will be approached for enrollment• A total of 15 evaluable patients with untreated, advanced stage ovarian cancer undergoing neoadjuvant chemotherapy will be treated with olaparib 300mg (tablet formation) by mouth twice a day (PO BID) for 2 cycles. Each cycle will be 28 days long. Following 2 cycles of Olaparib, patients with no evidence of tumor progression will have tumor reductive surgery and then receive standard cytotoxic chemotherapy within 3-6 weeks of surgery according to provider discretion. Patients with tumor progression or responsive disease not amenable to surgery will undergo tumor biopsy then proceed to standard cytotoxic chemotherapy with goal of getting patients to a respectable state. • Patients will have their laparoscopic tumor evaluation after receiving 2 cycles of neoadjuvant therapy. Patients scored as <10 by the validated scoring system (ability to resect to no gross residual disease) will proceed to primary tumor reductive surgery followed by physician’s choice cytotoxic chemotherapy.  Patients scored ≥ 10 will receive physician’s choice cytotoxic chemotherapy with the goal of subsequent tumor reductive surgery (Figure 3)Trial Design Patient SelectionPS, Performance Status; Bx, Biopsy; CA125, Cancer Antigen 125; BRCA, Breast Cancer Susceptibility Gene; Physician’s Choice, Adjuvant therapy at the discretion of the treating physicianCharacteristic Olaparib/Total(n=14)Age, median (range) 58.3 (44-88)Ethnicity, n (%)Hispanic/LatinaNot Hispanic/LatinaUnknown3 (21.4)10 (71.4)1 (7.1)Race, n (%)White/CaucasianAsianBlackNative American/Pacific IslanderOther10 (71.4)0 (0)1 (7.1)0 (0)3 (21.4)Stage, n (%)IIIIVN/A6 (42.9)2 (14.3)6 (42.9)Histology, n (%)High grade serous 14 (100)Mutation, n (%)BRCA1BRCA2RAD51CRAD51DPALB210 (71.4)2 (14.3)1 (7.1)0 (0)1 (7.1)• Primary Objective: • To determine  feasibility of daily olaparib given in neoadjuvant setting in women with primary advance ed high grade non-mucinous epithelial ovarian, fallopian tube, or primary peritoneal cancer• Secondary Objectives: 1. Efficacy of neoadjuvant olaparib by using response rate,2. Proportion of subjects able to proceed to TRS (tumor reductive surgery) without chemotherapy3. Determine progression free survival (PFS),4. Complete pathologic response at interval TRS,5. Toxicity of olaparib in neoadjuvant setting,6. Toxicity of chemotherapy after neoadjuvant Olaparib, and7. Longitudinal symptom burden of patients treated with neoadjuvant olaparib and adjuvant chemotherapy• Exploratory Objectives: 1. Explore genetic material and protein expression in HR related pathways before and after treatment with olaparib2. Correlate molecular results with clinical endpoints including response and survival Figure 3. Study SchemaFigure 2. Cytology of High Grade Serous Ovarian Cancer [7]Table 1. Patient Demographics and Clinical FeaturesCytological features of high-grade serous cancer. (A): Multinucleated tumor giant cells; (B): severe pleomorphism and prominent nucleoli; (C): frequent mitotic figures; (D): psammoma bodies. All original magnifications × 40.Figure 1. Mechanism of sensitivity to olaparib in cells with HR deficiencies [6]Inclusion criteria:• Age ≥ 18 years at time of signing informed consent • Histology showing high-grade epithelial non-mucinous ovarian, primary peritoneal, or fallopian tube cancer• Documented germline, or somatic testing by ctDNA, BRCA 1/2, RAD51C/D, PALB2• No prior treatment for primary advanced (Stage III or IV) epithelial ovarian, primary peritoneal, or fallopian tube carcinoma such as irradiation, chemotherapy, hormonal therapy, immunotherapy, investigational therapy, surgery, and/or other concurrent agents or therapies• A disposition to neoadjuvant chemotherapy with planned interval tumor reductive surgery after 3 complete cycles of treatment• Have measurable disease based on RECIST 1.1. Evaluable disease includes nonmeasurable lesions, ascites, pleural effusion• Peripheral neuropathy Grade 0 or 1 by CTCAE v5.0• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1• Life expectancy of ≥ 16 weeks• Postmenopausal or evidence of non-childbearing status. Women of childbearing potential must utilize acceptable contraception for two weeks before the first dose of Olaparib, the duration of the study, and at least for six months after the last dose of olaparib• Adequate normal organ and marrow functionObjectivesPatient Selection• Exclusion criteria:• Prior treatment for ovarian, fallopian tube, or primary peritoneal cancer• Histology showing mucinous or low-grade epithelial carcinoma• Presence of other active invasive cancers• Resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator• Any unresolved toxicity (>CTCAE grade 2) from previous anti-cancer therapy, excluding alopecia• History of hypersensitivity to olaparib or its excipients• Uncontrolled intercurrent illnesses• Subjects who are pregnant and/or breast-feeding• History of leptomeningeal carcinomatosis, uncontrolled or symptomatic brain metastasis or uncontrolled seizures• Patients with Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) or with features suggestive of MDS/AML• Previous treatment with PARP inhibitor, including olaparib• Patients unable to swallow orally administered medication or patients with GI disorders likely to interfere with absorption of study drug• Concomitant use of known strong or moderate CYP3A inhibitors or inducers• Major surgery within two weeks of starting study treatment• Previous allogenic bone marrow transplant, double umbilical cord blood transplant• Whole blood transfusions in the last 120 days prior to entry to the studyFuture DirectionsReferences:1. Coleman, R.L., et al., Latest research and treatment of advanced-stage epithelial ovarian cancer. Nat Rev Clin Oncol, 2013. 10(4): p. 211-24. 2. Burger, R.A., et al., Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med, 2011. 365(26): p. 2473-83. 3.. Drew, Y., et al., Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer. Br J Cancer, 2016. 114(12): p. e21. 4. 15. Integrated genomic analyses of ovarian carcinoma. Nature, 2011. 474(7353): p. 609-15. 5. Ledermann, J., et al., Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med, 2012. 366(15): p. 1382-92. 6. Annunziata, Christina M. and Susan E. Bates. “PARP inhibitors in BRCA 1 / BRCA 2 germline mutation carriers with ovarian and breast cancer.” (2010). 7. Lisio MA, Fu L, Goyeneche A, Gao ZH, Telleria C. High-Grade Serous Ovarian Cancer: Basic Sciences, Clinical and Therapeutic Standpoints. Int J Mol Sci. 2019 Feb 22;20(4):952The results of this study will help researchers and clinicians in their approach to find efficacious treatment for high grade primary epithelial ovarian cancer. The results will provide new insight on ways to personalize treatment for primary epithelial  ovarian cancer by different strata, in this case genetic mutations in HR repair. Because little substantive progress has been made in the treatment and management of primary epithelial ovarian cancer in the last 30 years, it is crucial for researchers to use this data to reshape the necessary scientific models so that cancer medicine can take a step in the right direction in innovating new treatment regimens for this subset of gynecologic malignancies.

Feasibility Study of Neoadjuvant Olaparib for Frontline BRCA Mutant Ovarian Cancer

https://openworks.mdanderson.org/cgi/viewcontent.cgi?article=1095&context=sumexp22

Feasibility Study of Neoadjuvant Olaparib for Frontline BRCA Mutant Ovarian Cancer

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