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2021 Master Class CourseMolecular Advances and Emerging Treatment Strategies in Ovarian CancerUrsula Matulonis, MDChief, Division of Gynecologic OncologyBrock-Wilson Family Chair Dana-Farber Cancer InstituteProfessor of MedicineHarvard Medical School
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Faculty Disclosure• Consulting: NextCure, Astrazeneca• Advisory Boards: Novartis, Blueprint Medicines, Trillium• Scientific Advisory Board Member: Clearity Foundation, Rivkin Foundation
and Ovarian Cancer Research Alliance• Data Safety Monitoring Boards: Symphogen, Advaxis
Faculty of this CE activity may include discussions of products or devices that are not currently labeled for use by the FDA.The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off label or investigational uses (any uses not approved by the FDA) of products or devices.
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Incidence and prevalence in U.S. women
• 21,410 new cases estimated for 2021;incidence is dropping
• Remains the second most common gyn tumor in the U.S.
• ~235,000 women living w/ ovarian cancer in U.S.
Mortality in U.S. women• 13,770 estimated deaths in
2021; survival is improving• 5th most common cause of
cancer death in women
Ovarian Cancer 2021
Siegal et al, 2021SEER.gov (accessed 9/24/21)
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Newly diagnosed ovarian cancer management: 2021• Basic principles
• Surgery by a gynecologic oncologist is associated with improved survival1• Extent of cytoreduction (debulking) is classified by residual disease following surgery
• Suboptimal: >1 cm of residual tumor• Optimal: ≤1 cm of residual tumor• NED (R0): No gross residual disease
• Considerations in the approach to initial disease treatment• Upfront surgery versus neoadjuvant treatment decision should be made by a gyn onc surgeon• Multiple randomized trials show equivalency of upfront surgery versus neoadjuvant, but ability
to do upfront surgery is associated with a better outcome • Optimal schedule of carboplatin and paclitaxel: q3 week = weekly• Addition of bevacizumab to carbo/paclitaxel + maintenance prolongs PFS but not OS• Histology specific treatment• HIPEC: only used at high volume centers; median overall survival was 33.9 months in the
surgery group and 45.7 months in the surgery-plus-HIPEC
1Cliby WA, Gynecol Oncol. 2015, Wright et al Gyn Onc 20162Moore et al, NEJM 2018, Van Driel et al, NEJM 2018, Coleridge 2021
5NCCN guidelines 2020; adapted from FIGO Staging System for Ovarian, Fallopian Tube, and Primary Peritoneal Cancer (8th ed., 2017)
Ovarian Cancer Staging
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Classification of ovarian cancer includes molecular data
High grade serous or endometrioid
Low grade endometrioid
Low gradeserous
Clear Cell Mucinous
Genetic characteristics
Up to 50% have HRDAssociated with TP53 and BRCA mutations
PTEN, ARID1A, PIK3CAalterations
May have Microsatellite instability
KRAS, BRAF mutations
PIK3CA, ARID1A, PTEN
KRAS; may have microsatellite instability
Clinicalcharacteristics
Platinum and PARP inhibitor sensitivity
Carcinosarcomas are treated like high grade serous cancers
Potentially more responsive to hormonal therapy, although not established
Hormonaltherapies
MEK inhibitors
May be more sensitive to immumotherapy
Are more resistant to chemotherapy
TCGA, 2011; Ilenkovan/Gourley 2018; Ryland et al, 2015; Stany et al, 2011; Hunter et al, 2015
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2020 Germline and Somatic Tumor Testing in Epithelial Ovarian Cancer: ASCO Guidelines
• All women diagnosed with epithelial ovarian cancer should have germline Panel testing at diagnosis.
• Somatic tumor testing for BRCA 1 and 2 should be performed in women who do not carry a germline abnormal BRCA1/2 gene mutations-- 11 recognized hereditary mutations: BRCA1, BRCA2, MSH2, MLH1, PMS2,
PALB2, BARD1, RAD51C, RAD51D, and BRIP1-- 15% of women with high grade serous ovarian cancer have germline BRCA
mutations-- 6% of patients with high grade serous histology have somatic BRCA mutations
• Women diagnosed with clear cell, endometrioid, or mucinous ovarian cancer should be offered somatic tumor testing for mismatch repair deficiency (dMMR).
Konstantinopoulos et al JCO 2020SGO guidelines, NCCN genetics guidelinesNorquist et al, JAMA Oncology 2016;2:484-490
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ICON8: Carboplatin and paclitaxel chemotherapy: All schedules are equivalent (A); Pts receiving neoadjuvant treatment had worse outcomes (B)
Carboplatin/paclitaxel every 21 days (Standard) 17.7
Carboplatin every 21 days/paclitaxel weekly 20.8
Weekly carboplatin and weekly paclitaxel 21.0
PFS in monthsPFS for All patients (A)
Clamp et al, Lancet 2019Bladgen et al, Lancet Onc 2020
Patients undergoing upfront cytoreductive surgery had better outcomes (PFS)
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Addition of bevacizumab to chemotherapy and used as maintenance extends PFS in newly diagnosed advanced ovarian cancer; no OS benefit
14.1 vs. 11.2 vs. 10.3 mos
FDA approval in June 2018; PFS improvement based on censoring patients with CA125-based progression;~6 month improvement in PFS with addition of bev to chemotherapy and as maintenance
GOG218Stages eligible:III (macroscopic, ≤1 cm)III (> 1cm)IVBev dose is 15 mg/kg; started at cycle 2 and continued for 22 cycles
Burger et al., NEJM 2011, Avastin FDA PI, Tewari et al, JCO 2019
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Does longer bevacizumab duration impact outcomes? No
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Mechanisms of Action• Inhibit the function of PARP• Formation of PARP-DNA complexes through PARP
trapping
Cannot be combined easily; doses/schedules need to be adjusted because of observed myelosuppression
PARP Inhibitors
Thomas A, et al. J Clin Invest. 2018; Matulonis UA, Monk BJ. Ann Oncol. 2017.
Can be more easily combined with chemotherapy
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First-Line Maintenance: SOLO-1 Trial
Moore K, et al. N Engl J Med. 2018;379:2495-2505.
• Newly diagnosed stage III/IV, high-grade serous or endometroid ovarian, primary peritoneal, or fallopian tube cancer
• Germline or somatic BRCAm• Cytoreductive surgery or
attempt either before chemo or interval
• Cancer showed a response to platinum-based chemotherapy
Olaparib 300 mg bd(N=260)
Placebo(N=131)
2:1 randomization
Primary Endpoint
• Investigator-assessed progression free survival or how well and long the cancer stays in remission for
Two years’ treatment if no evidence of disease
• Study treatment continued until disease progression
• Patients with no evidence of disease at 2 years stopped treatment
• Patients with PRat 2 years could continue treatment
Study Design
14Gonzalez-Martin et al., N Engl J Med 2019, ESMO 2019
15Ray-Coquard et al., ESMO 2019, N Engl J Med 2019; 381:2416-2428
PAOLA-1
Primary Endpoint
• Investigator-assessed progression free survival or how well and long the cancer stays in remission for
161Moore et al, NEJM 2019, 2Gonzalez-Martin NEJM 2019, 3Ray-Coquard NEJM 2019
Upfront PARP inhibitor studies in advanced ovarian cancer
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Newly Diagnosed ovarian cancer: BRCA mutated
Moore et al, NEJM 2019, Gonzalez-Martin NEJM 2019, Ray-Coquard NEJM 2019
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ESMO 2020 update: No additional cases of MDS/AML reported.Incidence <1.5% (3/260), no cases in placebo arm
5 year follow-up: Improvement in PFS with Olaparib compared to placebopersists in women with advanced BRCA mutated ovarian cancer
NEJM 2018, ESMO 2020, SGO 2021
Olaparib(N=260)
Placebo(N=131)
Events (%) [50.6% maturity] 102 (39.2) 96 (73.3)
Median PFS, months NR 13.8
HR 0.3095% CI 0.23, 0.41;
P<0.0001
Initial results ESMO 2018
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Newly diagnosed ovarian cancer: BRCAwt/HR deficient (HRD)
Gonzalez-Martin NEJM 2019, Ray-Coquard NEJM 2019
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Newly diagnosed ovarian cancer: BRCAwt/HR proficient (HRP)
Gonzalez-Martin NEJM 2019, Ray-Coquard NEJM 2019
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Histology specific treatment: Low grade Serous Cancer
• High proportion of LGSC’s have estrogen and progesterone receptor expression• Hormonal therapy has efficacy in recurrent LGSC• Gershenson et al: retrospective study of 203 patients (stage II to IV) LGSC
treated with surgery followed by platinum-based chemotherapy• Retrospective analysis 2 groups: no maintenance therapy versus hormonal
therapy• Results: PFS higher for women receiving hormonal therapy (most rec’d an AI)
than patients receiving no maintenance:
Hormonal therapy: 64.9 monthsObservation: 26.4 months
Gershenson et al, JCO 2017
NRG-GY019 (NCT04095364) is open currently: Letrozole versus Paclitaxel/Carboplatin/Letrozole in Treating Patients With Stage II-IV Ovarian or Primary Peritoneal Cancer
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Recurrent Ovarian Cancer• The majority of patients with advanced stage ovarian cancer will recur• Recurrences (in US) most often detected by rising CA125
• Follow-up typically every 3 months for first 2 years, every 6 months for next 3 years following initial treatment
• Recurrences defined by time since initial platinum-based therapy• Platinum-refractory: failed to achieve at least a partial response to therapy/growth on
platinum or growth within 4 weeks of platinum completion• Platinum-resistant: recurrence within 6 months of last platinum-based therapy• Platinum-sensitive: recurrence more than 6 months after last platinum-based therapy
• Can also treat per “platinum appropriate” or “not appropriate”• FDA approved treatments
• Chemotherapy +/- bevacizumab• PARP inhibitors
Salani R, Am J Obstet Gynecol. 2011;204:466-78
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Addition of Bevacizumab to non-platinum chemotherapy in recurrent platinum-resistant ovarian cancer increases PFS: the AURELIA trial
Chemotherapy options: Paclitaxel 80 mg/m2 on Days 1,8,15, 22 every 28 days Topotecan 4 mg/m2 on Days 1, 8 ,15 every 28 days or Topotecan 1.25 mg/m2 on Days 1-5 every 21 days Pegylated liposomal doxorubicin (PLD) 40 mg/m2 on Day 1 every 28 days
Pts with measurable OC that progressed < 6 mos
from platinum-based chemotherapy;
≤ 2 prior therapies;no bowel involvement
(N = 361)
Disease progression
Nonplatinum Chemotherapy
Nonplatinum Chemotherapy + Bevacizumab
Stratified by chemotherapy, PFI (< 3 mos vs 3-6 mos),
prior anti-angiogenesis
Pujade-Lauraine et al., J Clin Oncol 2014 and 2015
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Bevacizumab + chemo improved PFS in platinum-resistant ovarian cancer: still represents the standard of care for plat resistant ovarian ca
Pujade-Lauraine et al. JCO 2014Poveda et al, JCO 2015
Weekly Pac
Weekly Pac + Bev
PLD PLD + Bev Topo Topo + Bev
ORR 30.2% 53.3% 7.8% 13.7% 0% 17.0%
PFS 3.9 mo 10.4 mo
HR 0.46 (CI 0.3-0.71)
3.5 mo 5.4 mo
0.57 (CI 0.39-0.83)
2.1 mo 5.8 mo
0.32 (0.21-0.49)
No overall survival benefit with adding bevacizumab to non-platinum chemotherapy
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Platinum sensitive recurrent ovarian cancer: Key studies of platinum doublets and triplets
Study Regimen(s) PFS OSCALYPSO1 (A) Carboplatin/paclitaxel
(B) Carboplatin/pegylated liposomal doxorubicin (PLD)
9.4 months11.3 monthsHR = 0.821 (95% CI 0.72–0.94; P = 0.005)
33 months30.7 monthsHR 0.99 (95% CI 0.85-1.16, p=0.94)
OCEANS2,3 (A) Carboplatin/gemcitabine (CG)(B) CG/bevacizumab + bevacizumab maintenance
8.4 mos12.4 mosHR 0.484 (95% CI 0.388 to 0.605; log-rank P < .0001)
32.9 months33.6 monthsHR 0.95 (95% CI: 0.77–1.18; log-rank p value = 0.65)
GOG2134 (A) Carboplatin/paclitaxel (CP)(B) CP/bevacizumab + bevacizumab maintenance
10.4 mos13.8 mosHR 0.628 (95% CI 0.534–0.739; p<0·0001)
37.3 mos42.2 mosHR 0.829 (95% CI 0.683-1.005; p=0.056)
AGO-OVAR2.21/ENGOT-OV184,5
(A) Carboplatin/PLD/bev + bevacizumab maintenance
(B) Carboplatin/gemcitabine/bevacizumab + bevmaintenance
13.3 mos11.7 months HR 0.807 (95% CI 0.681-0.956; p=0.0128)
33.5 months28.2 months HR 0.810 (95% CI 0.668-0.983, p=0.0319)
1Pujard Lauraine et al, JCO 2010, 2Aghajanian et al, JCO 2012 and 3Gyn Onc 2015, 4Coleman et al., Lancet Oncology 2017,5 Pfisterer et al, ESMO 2018/SGO 2019
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Strategies for platinum sensitive ovarian cancer
• Decision making needs to occur at the start of the platinum doubletand should include risks/benefits of these approaches
1Study 19, NEJM 2012, 2NOVA NEJM 20163SOLO2 Lancet Oncology 2017, 4ARIEL3, Lancet 2017, 5OCEANS, JCO 2015
Platinum chemotherapy
Bevacizumab maintenance4,5:
Platinum chemotherapy + bevacizumab Bevacizumab maintenance
PARP inhibitor maintenance
Platinum doublet chemotherapy
Platinum chemotherapy
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SOLO2/ENGOT-OV21 Study Schema
Pujade-Lauraine, Lancet Oncology, 2017
Placebon=99
Olaparib 300 mg bid
n=196Primary endpoint
Investigator-assessedPFS
Patients• BRCA1/2 mutation• Platinum-sensitive relapsed
ovarian cancer • At least 2 prior lines of
platinum therapy• CR or PR to most recent
platinum therapy
Random
ized2:1
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ENGOT-OV16/NOVA Trial Schema
gBRCAmut (N = 203)
Treat until Progression of Disease
Niraparib 300 mg once daily Placebo
Non-gBRCAmut (N = 350)
Treat until Progression of Disease
Niraparib 300 mg once daily Placebo
2:1 Randomization 2:1 Randomization
Platinum-Sensitive Recurrent High-Grade Serous Ovarian Cancer
Response to Platinum Treatment
Treatment with at least 4 Cycles of Platinum-based Therapy
Primary Endpoint: PFS by central, blinded review: results for both gBRCA and non-gBRCA groups analyzed simultaneously
Mirza, N Engl J Med 2016
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ARIEL3: STUDY DESIGN
• HRR status by NGS mutation analysis BRCA1 or BRCA2 Non-BRCA HRR gene†
None of the above• Response to recent platinum
CR PR
• Progression-free interval after penultimate platinum 6 to <12 months ≥12 months
Patient eligibility Stratification
• High-grade serous or endometrioid epithelial OC, primary peritoneal, or fallopian tube cancers
• Sensitive to penultimate platinum• Responding to most recent platinum
(CR or PR)* Excludes patients without assessable
disease following second surgery• CA-125 within normal range• No restriction on size of residual tumour• ECOG PS ≤1• No prior PARP inhibitors
PlaceboBID
n=189
Rucaparib 600 mg BID
n=375
Ran
dom
isat
ion
2:1
Lancet 2017
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Phase III PARP inhibitor maintenance studies show:1. Strikingly similar PFS results regardless of PARP inhibitor2. Decreasing benefits with “less” HRD: most benefit for women with BRCA mutated
ovarian cancer and the least for BRCA wild-type and HRD negative (i.e. HR proficient)
Trial ITT BRCAm HRD Positive BRCAwt and HRD Negative
PFS OS PFS OS PFS OS PFS OS
NOVA (BICR)Niraparib Pts were separated into
gBRCA and non-BRCAgroups
21 NR 12.9 NR 6.9 NRPlacebo 5.5 NR 3.8 NR 3.8 NR
Hazard ratio 0.27 0.38 0.58SOLO2 (Investigator-assessed)
Olaparib Only patients with BRCAm cancers
eligible
19.1 NRNA NAPlacebo 5.5 NR
Hazard ratio 0.30ARIEL3 (Investigator-assessed)
Rucaparib 10.8 NR 16.6 NR 13.6 NR 6.7 NRPlacebo 5.4 NR 5.4 NR 5.4 NR 5.4 NR
Hazard ratio 0.36 0.23 0.32 0.58
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Overall Survival results from SOLO2: 13 month improvement in overall survival
OS benefit was 16.3 months for Olaparib after adjusting for subsequent PARPinhibitor use:
Poveda, ASCO 2020
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Toxicities of PARP inhibitorsMyelosuppression Fatigue Gastrointestinal toxicities: i.e. Nausea, vomiting, diarrhea, constipation, reduced appetiteRisk of secondary AML or MDSup to 1.5% for women with newly diagnosed ovarian cancer2 to 8% for women with recurrent cancer
Examples of drug-specific side effects:Niraparib: hypertension, tachycardia, headachesOlaparib: pneumonitis, increase in creatinineRucaparib: transient increase in liver enzymes, increase in creatinine,
increase in cholesterol and risk of rash
FDA PI’s for Olaparib, niraparib, rucaparib
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Risk of AML/MDS w/ PARP inhibitors increases in women with ovarian cancer with BRCAm and recurrence
Study Clinical Setting AML/MDS risk in BRCA mutation carriers
AML/MDS risk in non-BRCA carriers
SOLO1 1st line upfront treatment
<1.5% n/a
SOLO2 Recurrent maintenance
8% n/a
NOVA Recurrent maintenance
6.6% 1.7%
Poveda et al, ASCO 2020, Lancet Onc 2021Matulonis et al, SGO 2021
SOLO2 8% 4%
NOVA
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Risk of AML/MDS w/ PARP inhibitors increases in women with ovarian cancer with BRCAm and recurrence
Study Clinical Setting AML/MDS risk in BRCA mutation carriers
AML/MDS risk in non-BRCA carriers
SOLO1 1st line upfront treatment
<1.5% n/a
SOLO2 Recurrent maintenance
8% n/a
NOVA Recurrent maintenance
6.6% 1.7%
Poveda et al, ASCO 2020, Lancet Onc 2021Matulonis et al, SGO 2021
SOLO2 8% 4%
NOVA
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Dose modifications for each PARP inhibitor
Initial Dose: 300 mg once daily
First Dose Reduction: 200 mg once daily
Second Dose Reduction: 100 mg once daily
Niraparib Olaparib RucaparibUse weight and platelet-based dosing (in FDA PI for PRIMA-approval; monitor blood counts weekly x 4 weeks, then monthly
Initial Dose: 600 mg twice daily
First Dose Reduction: 500 mg twice daily
Second Dose Reduction: 400 mg twice daily
Third Dose Reduction: 300 mg once daily
Initial Dose: 300 mg twice daily
First Dose Reduction: 250 mg twice daily
Second Dose Reduction: 200 mg twice daily
Monitor complete blood countat baseline and monthly thereafter
Monitor complete blood countat baseline and monthly thereafter
Berek et al, 2019
100 mgcapsules
100 and150 mg tabs
200, 250 mg, 300 mg tabs
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How PARP inhibitor approvals started in ovarian cancer:PARP Inhibitors Are Active as Single Agents in BRCAm recurrent Ovarian Cancer
Olaparib1 Rucaparib1 Niraparib1,2
BRCA status Mutated Mutated Mutated
# of lines of prior therapy At least 3 prior lines At least 2 prior lines (43% had 3 or more) at least 3 prior lines
Response rate 34% 54%(IRR 42%) 24%
Median duration of response 7.9 months 9.2 months(IRR 6.7 months) 8.3 months
1FDA Prescribing Information2Niraparib is also approved for platinum sensitive HRD ovarian cancer (3 or more prior lines)
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Special FDA package insert warnings and precautionsDrugNiraparib Test complete blood counts weekly for the first month, monthly for the next 11 months and periodically
thereafter for clinically significant changesCardiovascular Effects: 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 niraparib Manage with antihypertensive medications as well as adjustment of the niraparib dose, if necessary.
Olaparib Monitor patients for hematological toxicity at baseline and monthly thereafter
Pneumonitis: Occurred in <1% of patients exposed to Lynparza, and some cases were fatal. Interrupt treatment if pneumonitis is suspected. Discontinue if pneumonitis is confirmed. Venous thromboembolic events including pulmonary embolism occurred in 7% of patients with mCRPC. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate.
Rucaparib Monitor patients for hematological toxicity at baseline and monthly thereafter. Interrupt or reduce the dose based on severity of reaction.
All Monitor patients for hematological toxicity and discontinue if MDS/AML is confirmed
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Special FDA package insert warnings and precautionsDrugNiraparib Test complete blood counts weekly for the first month, monthly for the next 11 months and periodically
thereafter for clinically significant changes Cardiovascular Effects: 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 niraparib Manage with antihypertensive medications as well as adjustment of the niraparib dose, if necessary.
Olaparib Monitor patients for hematological toxicity at baseline and monthly thereafter
Pneumonitis: Occurred in <1% of patients exposed to Lynparza, and some cases were fatal. Interrupt treatment if pneumonitis is suspected. Discontinue if pneumonitis is confirmed.Venous thromboembolic events including pulmonary embolism occurred in 7% of patients with mCRPC. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate.
Rucaparib Monitor patients for hematological toxicity at baseline and monthly thereafter. Interrupt or reduce the dose based on severity of reaction.
All Monitor patients for hematological toxicity and discontinue if MDS/AML is confirmed
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Special FDA package insert warnings and precautionsDrugNiraparib Test complete blood counts weekly for the first month, monthly for the next 11 months and periodically
thereafter for clinically significant changes Cardiovascular Effects: 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 niraparib Manage with antihypertensive medications as well as adjustment of the niraparib dose, if necessary.
Olaparib Monitor patients for hematological toxicity at baseline and monthly thereafter
Pneumonitis: Occurred in <1% of patients exposed to Lynparza, and some cases were fatal. Interrupt treatment if pneumonitis is suspected. Discontinue if pneumonitis is confirmed. Venous thromboembolic events including pulmonary embolism occurred in 7% of patients with mCRPC. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate.
Rucaparib Monitor patients for hematological toxicity at baseline and monthly thereafter. Interrupt or reduce the dose based on severity of reaction.
All Monitor patients for hematological toxicity and discontinue if MDS/AML is confirmed
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Immune checkpoint inhibitors have only modest activity in Recurrent Ovarian Cancer
Agent Patients, n RR Median PFS Prior therapyNivolumab (JCO 2015)
20 patients 15% 3.5 months 55% had >3 lines of prior treatment
Avelumab (JAMA Onc2019)
125 patients 9.6% 2.6 months Median number of prior therapies was 4
Pembrolizumab(Annals of Oncology 2019)
376 patients 8%
Higher RR’s in PD-L1 +(CPS 10 or higher) compared to CPS<117.1% vs 5%;
2.1 months Pts grouped into cohort A (1-3 prior lines) and B (4-6 prior lines)
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Addition of Immunotherapy to chemotherapy shows no benefit in ovarian cancer
Newly diagnosed advanced cancerJavelin 100: Avelumab/carboplatin/paclitaxel Avelumab maintenance versus Avelumab/carboplatin/paclitaxel versus carboplatin/paclitaxel IMagyn50: atezolizumab/carboplatin/paclitaxel/bevacizumab vs carbo/pac/bev, both with bev maintenance
Recurrent platinum resistant:Javelin 200: PLD versus PLD/avelumab versus avelumab
SGO 2020, ESMO 2020, JCO 2021, Lancet Oncology 2021
Results: No PFS nor OS benefit for the addition of avelumab or atezolizumab to chemotherapy
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FDA-approved indications for immunotherapy in ovarian cancer
• Pembrolizumab:
2017 FDA approval for MSI-high/MMR deficient cancers
2020 FDA approval for Tumor Mutational Burden high
(≥10 mutations/megabase)
• MMR deficiency is quite rare in high grade serous ovarian cancer but more
common in non-serous ovarian cancer
Xiao et al, Gyn Onc 2014, Morice et al, NEJM 2019Konstantinopoulos et al, JCO 2020
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• Recurrent ovarian cancer• No prior gem or PLD• Up to one prior regimen
for platinum resistant cancer
• N=316• Primary: OS• Secondary: PFS, safety, ORR
Nivolumab 240 mg IV every 2 weeks
Gemcitabine 1000 mg/m2, days 1, 8, 15
OR
PLD 50 mg/m2
ESMO 2020; Abstract 807O; JCO 2021
NINJA trial (phase 3): ICI versus single agent chemotherapy for platinum resistant ovarian cancer:No improvement in OS with nivolumab compared with either gem or PLD
Results:
Median OS 10.12 months with nivolumab 12.09 months with GEM/PLD (NS HR 1.03, 95% CI, 0.80-1.32; P=0.808).
Median PFS2.04 months nivo3.84 months with GEM or PLD (HR 1.46; 95% CI, 1.15-1.85; P=0.002).
ORR:Was non-significantly lower in the nivolumab group (7.6% vs 13.2%; p=0.191).
JapicCTI-153004
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Mirvetuximab = folate receptor alpha, DM4
Annals of Oncology 2021
45Moore et al, ESMO 2019 Annals of Oncology 2021
46Moore et al, ESMO 2019
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Trials focused on platinum resistant high grade serous ovarian cancer with high FRα expression
MIRASOLNCT04209855 Phase III study1:1 to either mirvetuximab or investigator’s choice of single-agent chemotherapy Can have received up to 3 prior regimensPrimary endpoint is PFS
SORAYANCT04296890Single-arm trial with mirvetuximabCan have received up to 3 prior regimens (at least one of which included bevacizumab)Primary endpoint is ORR, and key secondary endpoint is duration of response.
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Arm ORR (95% CI)
SD PFS OS HR PFS(95% CI)
P-value
GOG239 Selumetinib
• KRAS mutant• KRAS WT
15%
14.3%25%
65% 11 mos NR NA NA
GOG281 TrametinibControl
26.2% 6.2%
59.2%70.8%
13.0 mo7.2 mo
37 mo29.2 mo
0.48 (0.36-0.64)
<0.0001
MILO BinimetinibControl
• KRAS mutant• KRAS WT
16%13%
9.1 mo10.6 mo
17.7 mo / 14.610.8 mo / 11.5(p=0.05 in bini)
28.0 mo25.0
1.21(0.79-1.86)
0.748
Farley Lancet Oncol 2013, Monk/Grisham IGCS 2019, JCO 2020, Gershenson ESMO 2019
• MEKi is an effective treatment modality in Low grade serous ovarian cancer• Relationship of RAS mutation status and response is not clearly defined.
Low grade serous ovarian cancer: single agent MEK inhibitors are active
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Thank you!
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