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ovarian cancer treatment

1. Stephanie Shuey, PharmD, BCOP Clinical Pharmacist – Gynecologic Oncology Duke University Medical Center Durham, NC Advances in Ovarian Cancer and Navigating the Evolving Therapy Choices

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3. Advances in Treatment-Naive Ovarian Cancer

4. Ovarian Cancer: Overview Fifth leading cause of cancer deaths in women despite only 1.1% of all new cancer cases 5-yr survival: 49% (overall), 30% (distant metastasis) 57% of women diagnosed have advanced-stage disease Median age at diagnosis is 63 yr 19,880 estimated new cases in 2022 National Cancer Institute. Surveillance, Epidemiology, and End Results (SEER) Program. seer.cancer.gov/statfacts/html/ovary.html.

5. Advanced Ovarian Cancer: Treatment Overview Kim. J Exp Clin Cancer Res. 2012;31:14. NCCN. Clinical practice guidelines in oncology: ovarian cancer. v.1.2023. nccn.org. Response rates up to 80% with frontline chemotherapy Relapse occurs in ~70% to 90% of women with advanced stage within 3 yr (median PFS ~18 mo ) Chemotherapy

6. Biomarker Subgroups Informing Treatment in Epithelial Ovarian Cancer One half of high-grade serous ovarian cancers exhibit a high degree of genomic instability due to deficiencies in homologous recombination All Ovarian (50% HRD + 50% HRP) HRD t BRC Am g BRC Am 13% (germline) 22% (somatic and germline) 50% HRD 50% are HRD, including BRCA m, BRCA 1/2, and RAD51 promoter methylation; BRIP1; and other genes involved in homologous recombination 22% are t BRCA m at diagnosis 13% are g BRCA m at diagnosis Cancer Genome Atlas Research Network. Nature. 2011;474:609. Konstantinopoulos. Cancer Discov. 2015;11:1137. Konstantinopoulos . JCO. 2020;38:1222. Mysona . SGO 2021. Poster 78. Studies demonstrate racial disparities in prevalence of genetic alterations: g BRCA 1 mutations: 16% Hispanic patients vs 7% White patients HRD mutations: ~30% Black and Asian patients vs 25% White patients

7. Current Guidelines for Genetic and Tumor Molecular Testing in Epithelial Ovarian Cancer Leading oncology societies recommend testing ALL women with ovarian cancer Only ~30% of women undergo any genetic testing Lower testing rates observed among Black and Hispanic patients compared to White patients and uninsured patients compared to insured patients Konstantinopoulos. JCO. 2020;38:1222. Kurian. JCO. 2019;37:1305. NCCN. Clinical practice guidelines in oncology: ovarian cancer. v.1.2023. nccn.org .

8. PARP Inhibitors in the First-Line and Maintenance Settings

9. Frontline Maintenance for Ovarian Cancer Following CR/PR to Platinum-Based Chemotherapy Maintenance Regimen Population BRCA m BRCA wt, HRD(+) BRCA wt, HRD(-) FDA Approved Olaparib +/- bevacizumab ✓ 2018 ✓* 2020 Niraparib ✓ 2020 ✓ 2020 ✓ 2020 Guideline Endorsed Rucaparib** ✓ ✓ ✓ Olaparib PI. Niraparib PI. Tew . JCO. 2022;40:3878. *Only in combination with bevacizumab. ** S upplemental NDA pending. HRD (-) HRD (+) BRCA wt 75% BRCA m 25% Niraparib and Rucaparib Olaparib + bevacizumab Olaparib

10. Frontline Maintenance: Key Phase III Clinical Trials PARPi Trial (N) Population PFS Hazard Ratio (95% CI) BRCA m BRCA wt, HRD(+) BRCA wt, HRD(-) Olaparib SOLO1 (N = 391) BRCA m stage III/IV HGS or endometrioid OC Response following PT-based CT 0.30 (0.23-0.41) — — Niraparib PRIMA (N = 733) Stage III/IV HGS or endometrioid OC Response following PT-based CT 0.40 (0.27-0.62) 0.50 (0.31-0.83) 0.68 (0. 49-0.94) Olaparib + Bev PAOLA-1 (N = 806) Stage III/IV HGS or endometrioid OC or g BRCA m nonmucinous epithelial OC Response following PT- taxane CT+ bev 0.31 (0.20-0.47) 0.43 (0.28-0.66) 1.00 ( 0.76-1.35) Rucaparib ATHENA -MONO (N = 538) Stage III/IV high grade EOC (any histology) Response following PT- taxane CT 0.40 (0.21-0.75) 0.58 (0.33-1.01) 0.65 (0.45-0.95) González-Martin. NEJM. 2019;381:2391 . Monk . JCO. 2022;40:3952. Moore. NEJM. 2018;379:2495 . Ray- Coquard . NEJM. 2019;381:2416.

11. Factors Influencing Choice of PARP Inhibitor

12. PARP Inhibitor Dosing and Interactions Olaparib Niraparib Rucaparib Dosage Forms 100 mg, 150 mg tablets 100 mg capsules 200 mg, 250 mg, 300 mg tablets Starting Dose 300 mg twice daily 300 mg daily 200 mg daily for weight <77 kg or platelet count <150K/ mcL * 600 mg twice daily Adjustments for Toxicity Level 1: 250 mg twice daily Level 2: 200 mg twice daily Level 1: 200 mg daily Level 2: 100 mg daily Level 1: 500 mg twice daily Level 2: 400 mg twice daily Level 3: 300 mg twice daily Duration of Frontline Therapy 2 yr 3 yr 2 yr Interactions Strong/moderate CYP3A4 inhibitors and inducers Avoid grapefruit and Seville oranges No significant drug interactions Sensitive substrates of CYP1A2, CYP3A, CYP2C9, or CYP2C19 NCCN. Clinical practice guidelines in oncology: ovarian cancer. v.1.2023. nccn.org. Niraparib PI. Olaparib PI. Rucaparib PI. *In first-line maintenance setting.

13. PARP Inhibitor Toxicities: Adverse Events of Interest Toxicity Type Implicated PARPi and Specific Toxicities Cardiovascular Niraparib : hypertension, tachycardia, palpitations Dermatologic Rucaparib > olaparib ≅ niraparib : rash Rucaparib : photosensitivity Gastrointestinal All agents : nausea, constipation, diarrhea, decreased appetite, dysgeusia ( rucaparib > olaparib and niraparib ), dyspepsia Hematologic All agents : anemia, neutropenia, thrombocytopenia ( niraparib > olaparib ≅ rucaparib ) . MDS/AML - i ncreased risk associated with treatment of recurrent disease, BRCA m , and duration of therapy >2 yr Hepatic Rucaparib > niraparib > olaparib : increased AST/ALT Musculoskeletal All agents : arthralgia, back pain Neurologic All agents : fatigue, headache, dizziness Niraparib > rucaparib > olaparib : insomnia Renal Olaparib and rucaparib : increased creatinine Respiratory All agents : dyspnea/cough, pharyngitis Olaparib : pneumonitis Armstrong. Gynecol Oncol. 2023;171:162. LaFargue . Lancet Oncol. 2019;20:e15. Madariaga A. Int J Gynecol Cancer. 2020;30:903. Niraparib PI. Olaparib PI. Rucaparib PI.

14. PARP Inhibitor Toxicities: Adverse Event Management Toxicity Type Hold Parameter Monitoring and Management Hematologic Hgb <8 g/dL and/or requiring transfusion PLT <100,000/mm 3 ANC <1000/mm 3 Weekly CBC until count recovery Resume PARPi at reduced dose Discontinue PARPi if inadequate improvement within 28 days or patient is on lowest dose Nonhematologic Grade > 3 or intolerable grade 2 toxicity despite medical management Hold PARPi until adequate improvement (eg, > 1 grade improvement in severity ) Resume PARPi at reduced dose for grade > 3 or recurrent grade 2 toxicity Discontinue PARPi for toxicity lasting >28 days at lowest dose LaFargue . Lancet Oncol 2019; 20:e15. Madariaga . Int J Gynecol Cancer. 2020; 30:903. Tew. JCO. 2020; 38:3468.

15. Navigating the Evolving Therapies for Relapsed Ovarian Cancer

16. Treatment of Relapsed Ovarian Cancer Platinum Refractory Disease Lack of response to first-line platinum therapy Poor prognosis Clinical trial recommended Consider targeted therapy based on molecular tumor testing NCCN. Clinical practice guidelines in oncology: ovarian cancer. v.1.2023. nccn.org . Platinum Sensitive Disease Relapse > 6 mo after completion of platinum therapy Combination platinum-based therapy preferred Consider platinum monotherapy if patient cannot tolerate combination therapy Platinum Resistant Disease Relapse <6 mo after completion of platinum therapy Nonplatinum regimen or agent preferred Combination therapy not preferred over single agent

17. Treatment of Relapsed Ovarian Cancer Platinum Sensitive Platinum Resistant Preferred Regimens Cytotoxic Therapy Carboplatin/paclitaxel +/- bev Carboplatin/liposomal doxorubicin +/-bev Carboplatin/gemcitabine +/- bev Cisplatin/gemcitabine Targeted Agents Bevacizumab Cytotoxic Therapy Paclitaxel (weekly) +/- bev Liposomal doxorubicin +/- bev Topotecan +/- bev Cyclophosphamide (oral) + bev Gemcitabine Etoposide (oral) Docetaxel Targeted Agents Bevacizumab Mirvetuximab soravtansine- gynx Clinical Considerations Regimen typically chosen based on toxicity profile, treatment history, and individual preference Addition of bevacizumab improves PFS (regardless of platinum sensitivity) and possibly OS (platinum-sensitive setting) but adds toxicity NCCN. Clinical practice guidelines in oncology: ovarian cancer. v.1.2023. nccn.org.

18. Role of PARP Inhibitors in Management of Relapsed Ovarian Cancer: Maintenance PARPi Population BRCA m BRCA wt, HRD(+) BRCA wt,HRD (-) Olaparib ✓ ✓ ✓ Niraparib ✓ g BRCA m only X* X* Rucaparib ✓ X* X* Maintenance following response to > 2nd line platinum-based chemotherapy Should only be offered to PARPi naive patients per ASCO guidelines Niraparib PI. Olaparib PI. Rucaparib. Tew . JCO.2022;40;3878 . *FDA approval withdrawn 12/2022.

19. Key Trials of PARPi Maintenance for Platinum Sensitive Ovarian Cancer STUDY 19 Olaparib vs Placebo All comers Median PFS (Mo) HR (95% CI) Overall : 8.4 vs 4.8 BRCA m : 11.2 vs 4.3 BRCA wt : 7.4 vs 5.5 0.35 (0.25-0.49) 0.18 (0.10-0.31) 0.54 (0.34-0.85) * Non- gBRCA group included sBRCA , BRCA wt/HRD (+), HRD (-). Ŧ HRD+ included sBRCAm , BRCAwt/HRD (+). Mo HR (95% CI) Overall : 29.8 vs 27.8 BRCA m : 34.9 vs 30.2 BRCA wt : 24.5 vs 26.6 0.73 (0.55-0.95) 0.62 (0.42-0.93) 0.84 (0.55-1.24) Coleman. Lancet. 2017;390:1949. Coleman. ESGO 2022. Abstract RA-249. Ledermann. NEJM. 2012;366:1382. Ledermann. Lancet Oncol. 2016;17:579. Matulonis . SGO 2023. Abstr 6. Mirza. NEJM. 2016;375:2154. Poveda. Lancet Oncol. 2021;22:620. Pujade-Lauraine . Lancet Oncol. 2017;18:1274. Median OS SOLO2 Olaparib vs Placebo BRCA m only Median PFS (Mo) HR (95% CI) Overall : 19.1 vs 5.5 0.30 (0.22-0.4) Mo HR (95% CI) Overall : 51.7 vs 38.8 0.74 (0.54-1.00) Median OS NOVA * Niraparib vs Placebo All comers Median PFS (Mo) HR (95% CI) g BRCA : 21.0 vs 5.5 Non- g BRCA : 9.3 vs 3.9 HRD+ : 12.9 vs 3.8 0.27 (0.17-0.41) 0.45 (0.34-0.61) 0.38 (0.24-0.59) Mo HR (95% CI) g BRCA : 40.9 vs 38.1 Non- g BRCA : 31.0 vs 34.8 HRD+ : 35.6 vs 41.1 0.85 (0.61-1.20) 1.06 (0.81-1.37) 1.27 (0.85-1.29) Median OS ARIEL3 Ŧ Rucaparib vs Placebo All comers Median PFS (Mo) HR (95% CI) BRCA m : 16.6 vs 5.4 HRD+ : 13.6 vs 5.4 ITT : 10.8 vs 5.4 0.23 (0.16-0.34) 0.32 (0.24-0.42) 0.36 (0.30-0.45) Mo HR (95% CI) BRCA m : 45.9 vs 47.8 HRD+ : 40.5 vs 47.8 ITT : 36.0 vs 43.2 0.83 (0.58-1.19) 1.01 (0.76-1.32) 1.00 (0.81-1.22) Median OS

20. Role of PARPi in Management of Relapsed Ovarian Cancer: Treatment Withdrawn indications based on new and emerging clinical data ARIEL-4 (rucaparib): FDA withdrawal of rucaparib for treatment of BRCA -mutated EOC after ≥2 previous lines of chemotherapy (June 10, 2022) Detriment to OS with rucaparib vs chemotherapy (19.4 vs 25.4 mo) SOLO-3 ( olaparib ): manufacturer voluntarily withdrew indication for treatment in germline BRCA mutant treated with ≥3 previous lines of chemotherapy (August 26, 2022) No difference in OS for olaparib vs chemotherapy (34.9 vs 32.9 mo) QUADRA (niraparib): manufacturer voluntarily withdrew niraparib’s indication for treatment in HRD positive EOC and ≥ 3 previous chemotherapies (September 14, 2022) Niraparib PI. Olaparib PI. Rucaparib PI. Tew. JCO. 2022;40;3878.

21. Mirvetuximab soravtansine PI. Moore. Ann Oncol. 2021;32:757. FDA approval FRα-positive ovarian, fallopian tube, or primary peritoneal cancer refractory or resistant to platinum-based chemotherapy after 1-3 previous chemotherapies Target: FRα Expressed on ~90% of OC Highly expressed on ~35% of OC Cytotoxic component: maytansinoid /DM4 Highly potent tubulin destabilizer Mirvetuximab Soravtansine in Relapsed Ovarian Cancer: FR α Target FR α Antibody Maytansinoid (DM4) Antibody Drug Conjugate Cleavable Sulfo-SPDB Linker (glutathione)

22. Matulonis. SGO 2022. Abstr 242. Matulonis. JCO.2023;[Epub]. Mirvetuximab Soravtansine in Platinum-Resistant OC and High FR α Expression (SORAYA): Phase III Trial Outcomes Outcome Investigator Assessed (N = 105) BICR Assessed (N = 96) ORR, n (%) [95% CI] 34 (32.4) [23.6-42.2] 29 (30.2) [21.3-41.4] Best overall response, n % CR PR SD PD Not evaluable 5 (4.8) 29 (27.6) 48 (45.7) 20 (19.0) 3 (2.9) 6 (6.3) 23 (24.0) 54 (56.3) 9 (9.4) 4 (4.2) Median DoR, mo (95% CI) 6.9 (5.6-9.7) NR (5.0-NR) Median PFS, mo (95% CI) 4.3 (3.7-5.2) 5.5 (3.8-6.9)

23. Phase III SORAYA Mirvetuximab Soravtansine: Safety Summary Most ocular and GI AEs low-grade and reversible Grade ≥3 TRAEs: D ose delay: 33% D ose reduction: 20 % Discontinuation: 9% One death possibly related to study drug Respiratory failure Autopsy: no evidence of drug reaction; lung mets No appreciable myelosuppression and limited low-grade neuropathy Matulonis. SGO 2022. Abstr 242. Matulonis. JCO.2023;[Epub]. TRAE, n (%) Mirvetuximab Soravtansine Any Grade Grade 3/4 Patients with any event 91 (86) 31 (29) Blurred vision 43 (41) 6 (6) Keratopathy 31 (29) 9 (9) Nausea 31 (29) 0 (0) Dry eye 26 (25) 2 (2) Fatigue 25 (24) 1 (1) Diarrhea 23 (22) 2 (2) Asthenia 16 (15) 1 (1) Photophobia 14 (13) 0 (0) Peripheral neuropathy 14 (13) 0 (0) Decreased appetite 14 (13) 1 (1) Vomiting 12 (11) 0 (0) Neutropenia 14 (13) 2 (2)

24. MIRASOL: Phase III Trial of Mirvetuximab Soravtansine vs Chemotherapy in Platinum-Resistant Disease Moore. ASCO 2023. Abstr LBA5507. Patients (%) Mirvetuximab Soravtansine (n = 227) Chemotherapy (n = 226) mPFS, mo (95% CI) 5.62 (4.34-5.95) 3.98 (2.86-4.47) HR (95% CI) 0.65 (0.52-0.81) P value <.0001 1.0 0.8 0.6 0.4 0.2 3 6 9 12 15 18 21 24 27 Mo Mirvetuximab soravtansine Chemotherapy Censored 227 226 151 98 89 48 38 19 18 5 10 3 3 2 3 1 1 Patients at Risk, n Mirvetuximab soravtansine Chemotherapy PFS by Investigator (Primary Endpoint)

25. Recommended Use of Eye Drops in Patients Receiving Mirvetuximab Soravtansine Mirvetuximab soravtansine PI. Infusion Cycle Day -1 Days 1-4 Days 5-8 Date Before infusion Infusion day After infusion 1 drop (per eye) of topical steroid eye drops 6 times/day ‒ 1 drop (per eye) of topical steroid eye drops 4 times/day ‒ ‒ Preservative-free lubricating eye drops 4 times/day + as needed As needed Note: counsel patients to use topical steroids ≥10 min before lubricating eye drop use; eye exams are recommended at baseline and then before cycles 3, 5, 7; counsel patients to avoid contact lenses S S L Providers should facilitate available resources to all patients, particularly those patients requiring financial assistance for molecular testing or treatment coverage

26. Role of PARPi With Targeted Therapies: Rationale for Combination Therapy Goal = enhance efficacy and combat resistance Bonadio . Front Oncol. 2021;11:754524. Konstantinopoulos . ASCO Educ Book. 2020;40:3116. Pina. IJGC. 2023;33:364. Vikas. Front Oncol. 2020;10:570.

27. Role of PARPi With Other Targeted Therapies: Key Trials in Recurrent Ovarian Cancer Study, Phase ( Yr ) N Results Conclusions and Notes Platinum Sensitive AVANOVA2, PhII (2019): niraparib (N) +/- bevacizumab (Bev) (PARPi + VEGF) 97 PFS (N + Bev vs Bev): 11.9 vs 5.5 mo ; HR: 0.35 Non- gBRCA m : 11.3 vs 4.2 mo ; HR: 0.32 g BRCA m : 14.4 vs 9.0 mo ; HR: 0.49 N + Bev demonstrated significant PFS benefit NCCN category 2B GY004, PhIII (2020): platinum-based Ct (PT-Ct) vs olaparib (O)+/- cediranib (Ce) (PARPi + VEGF) 565 PFS (O + Ce vs PT-Ct) : 10.4 vs 10.3 mo ; HR: 0.86 g BRCA m : HR: 0.55; 95% CI: 0.32-0.94 Non- g BRCA m : HR: 0.97; 95% CI: 0.73-1.30 O + Ce did not improve PFS and reduced PROs compared to PT-Ct MEDIOLA (2020), PhII : olaparib (O) + durvalumab (Du) +/- Bev (PARPi + PD-L1 + VEGF) 63 Non- g BRCA m (O + D vs O + D + Bev) 24 wk DCR : 28.1% vs 77.4% ORR : 31.3 vs 77.4% PFS: 5.5 vs 14.7 mo O + Du + Bev showed promising activity in non- g BRCA m disease Platinum Resistant MOONSTONE, PhII (2022): N + dostarlimab (Do) (PARPi + PD-1) 41 Non- g BRCA m ORR: 7.3% PFS . 2.1 mo Futility declared based on ORR OPAL, PhII (2021): N + Do + Bev (PARPi + PD-1 + VEGF) 41 ORR: 17.9% PFS : 7.6 mo N + Do + Bev showed clinical activity in PROC in a primarily BRCAwt/HRD (-) population Drew. Ann Oncol. 2020;31:S615. Liu. JCO. 2022;40: 2138. Liu. Gynecol Oncol. 2021;162:S17. Mirza. Lancet Oncol. 2019;20:1409. Randall. JCO. 2022;40:Abstr 5573. PARP inhibitors in combination with targeted therapies show activity in recurrent ovarian cancer Further research is required to determine which populations are most likely to benefit Phase III randomized trials needed to confirm efficacy and safety relative to standard of care chemotherapy Ongoing studies examining combination therapy for first line maintenance

28. PARP Inhibition Following Previous PARP Inhibition Study ( Yr ) Patients/Setting N Results OReO /ENGOT Ov-38 (2021): olaparib vs placebo PSOC following response to Pt-based CT and 1 prior line of PARPi maintenance 220 PFS (olaparib vs placebo) BRCA m : 4.3 vs 2.8 mo , HR: 0.57 ( P = .022) BRCA wt: 5.3 vs 2.8 mo , HR: 0.43, ( P = .002) EFFORT (2021): adavosertib ± olaparib (Wee1 + PARPi ) Recurrent epithelial ovarian cancer with progression on PARPi 80 Adavosertib alone ORR: 23% Adavosertib + olaparib ORR: 29% Median DoR (both arms): 5.5 mo CAPRI (2022) : Ceralasertib + olaparib ( ATRi + PARPi) HRD PSOC with progression on PARPi 13 ORR : 46% Pudaje-Lauraine . ESMO 2021. Abstr LBA33. Westin. ASCO 2021. Abstr 5505. Wethington. JCO. 2021;39;Abstr 5516.

29. Key Takeaways Leading oncology societies recommend genetic testing for all women with ovarian cancer Most patients will require additional treatment following frontline treatment, which can be personalized based on genetic and tumor molecular testing results Pharmacists involved in the care of patients with ovarian cancer can optimize outcomes by understanding the nuances of frontline and maintenance therapies, guiding therapy selection for relapsed disease based on patient characteristics, and incorporating approaches to foster equitable care across underserved and vulnerable patients

30. Go Online for More ProCE/CCO Education on Ovarian Cancer! ACPE-certified microlearning modules on pharmacist care for patients with ovarian cancer Expert commentaries providing key takeaways from the microlearning modules proce.com