A New String to the Bow in the Treatment of Advanced Ovarian Cancer Bradley J. Monk, MD, FACS, FACOG Arizona Oncology (US Oncology Network) Professor, Gynecologic Oncology University of Arizona and Creighton University
Fong PC, et al. N Engl J Med. 2009;361(2):123-134. Phase I: Olaparib (2009)
Olaparib: Early Clinical Activity Phase I MTD 400 mg twice daily Expansion phase (N = 39 BRCA+) = responses Platinum-sensitive > resistant Platinum-Free Interval 24 CR/PR 18 12 6 0 Sensitive Resistant Refractory SD >4 mo PD CR, complete response; PD, progressive disease; SD, stable disease Fong PC, et al. N Engl J Med. 2009;361(2):123-134.
Olaparib vs PLD: Study Design (2012) Primary objective: Compare efficacy (PFS) of 2 dose levels of olaparib (200 mg and 400 mg BID) with PLD Patients BRCA1/2 germline carriers with ovarian cancer Progressive or recurrent disease <12 months after previous platinum-based chemotherapy R 1:1:1 Olaparib 200 mg BID in 28-day cycles Olaparib 400 mg BID in 28-day cycles PLD 50 mg/m 2 IV every 4 weeks PD or withdrawal from treatment for other reason As above or max lifetime cumulative dose reached Stats: HR 0.55 (median PFS of 4 to 7.3 months) N planned: 90 (30/arm) Patients in PLD group were allowed to cross over to olaparib 400 mg BID on confirmed PD Kaye SB, et al. J Clin Oncol. 2012; 30(4):372-379.
Progression-Free Survival: Olaparib vs PLD Kaye SB, et al. J Clin Oncol. 2012; 30(4):372-379.
Study 42: Objective Response All patients 3 prior lines of therapy Anticipated response: <10% Kaufman B, et al. J Clin Oncol. 2015;33(3):244-250.
olaparib
EU Approval: Olaparib/Study 19 EMA Approval: December 16, 2014 Whole Population With HGSOC Subpopulation With BRCA Mutation P <.001 P <.0001 Ledermann J, et al. N Engl J Med. 2012;366(15):1382-1392. Ledermann J, et al. Lancet Oncol. 2014;15(8):852-861.
Olaparib in gbrca and BRCA wt Ovarian Cancer (2011) Ovarian gbrca Ovarian BRCA wt gbrca, platinum resistant or refractory gbrca, platinum sensitive BRCA wt, platinum resistant or refractory BRCA wt, platinum sensitive Gelmon KA, et al. Lancet. 2011; 12:852-861.
Why Would PARP Inhibitors Work in BRCA wt Patients? BRCA mut 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 BRCA wt 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Hypothesis 1: Ovarian cancer patients with high genomic LOH suggesting BRCA-like signature will respond to PARPi BRCA wt 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Chromosome Number Hypothesis 2: Ovarian cancer patients who are biomarker negative (ie, with low genomic LOH) will not respond to PARPi
ARIEL2 (Rucaparib): PFS (2016) Median, months (95% CI) BRCA mut 12.8 (9.0-14.7) BRCA wt /LOH high 5.7 (5.3-7.6) BRCA wt /LOH low 5.2 (3.6-5.5) Subgroup Comparison HR (95% CI) P BRCA mut vs BRCA wt /LOH low 0.27 (0.16-0.44) BRCA wt /LOH high vs BRCA wt /LOH low 0.62 (0.42-0.90) <.0001 =.011 1. Coleman RL, et al. J Clin Oncol. 2016;34(15S): Abstract 5540. 2. Swisher EM, et al. Lancet Oncol. 2017;18(1):75-87.
Rucaparib: Response in the FDA Label Outcome Investigator-assessed n = 106 Objective response rate (95% CI) 54% (44% - 64%) Complete response 9% Partial response 45% Median duration of response (95% CI) 9.2 months (6.6-11.6)
Switch Maintenance Induction therapy defined as platinum or platinum combination Clinical response is needed Measurable disease required at chemotherapy induction Partial response (PR) and CR are endpoints for randomization Usually a stratification variable Progression Chemo #2 M Chemo #3 M Chemo #4+ Death y
Platinum-Sensitive Relapse RCTs Maintenance After Chemotherapy Status Study 19 1 SOLO-2 2 NOVA 3 ARIEL3 4 Status Completed Completed Completed Completed Population HGSC gbrca mut II: Non-gBRCA I: gbrca mut HGSC 1. Ledermann J, et al. N Engl J Med. 2012;366: 1382-1392. 2. Pujade-Lauraine E, et al. Lancet Oncol. 2017;18(9):1274-1284. 3. Mirza MR, et al. N Engl J Med. 2016;375:2154-2164. 4. Coleman RL, et al. Lancet. 2017 Sept 12. [Epub ahead of print] HGSC or endometrioid Design Phase II Phase III Phase III Phase III Regimen Olaparib vs placebo Olaparib vs placebo Niraparib vs placebo Rucaparib vs placebo Primary endpoint PFS PFS PFS PFS N (randomization) 265 (2:1) HGSC, high-grade serous carcinoma, RCT, randomized control trials 295 (2:1) 469 (2:1) 540 (2:1)
SOLO-2: Study Design (2017) Patients BRCA mut ovarian cancer 2 previous platinum regimens Last chemotherapy platinum-based in CR/PR R 2:1 n = 295 Olaparib 300 mg BID (n = 196) Placebo BID (n = 99) Primary endpoint: PFS by investigator Key secondary endpoints: PFS2 (investigator assessed) OS Safety Patient-reported outcomes Key sensitivity analysis: PFS by blinded-independent review (BICR) 1. Pujade-Lauraine E, et al. Lancet Oncol. 2017;18(9):1274-1284. 2. Olaparib Treatment in BRCA Mutated Ovarian Cancer Patients After Complete or Partial Response to Platinum Chemotherapy. 3. National Institutes of Health, Available at: https://clinicaltrials.gov/ct2/show/nct01874353. Accessed October 12, 2017.
Platinum-Sensitive Relapse RCTs Maintenance After Chemotherapy: Olaparib Study Population N 19 (2012,2014,2016) Platinum-sensitive recurrent PFI, % Best platinum response, % 6-12 12+ CR PR 265 40 60 45 55 SOLO-2 (2017) gbrca 295 40 60 47 53 Study PFS PFS Other OS Notes 19 (2012,2014,2016) 8.4 vs 4.8 months 0.35 (0.25-0.49) SOLO-2 (2017) Investigator (I ) 19.1 vs 5.5 months 0.30 (0.22-0.41) PFI, platinum-free interval; BICR, blinded independent central review 1. Ledermann JA, et al. N Engl J Med. 2012;366:1382-1392. 2. Ledermann JA, et al. Lancet Oncol. 2014;15(8):852-861. 3. Ledermann JA, et al. J Clin Oncol. 2016;34(suppl): Abstract 5501. 4. Pujade-Lauraine E, et al. Lancet Oncol. 2017;18(9):1274-1284. BRCA mut (N = 136) 11.2 vs 4.3 months 0.18 (0.10-0.31) BICR 30.2 vs 5.5 months 0.25 (0.18-0.35) 29.8 vs 27.8 months 0.73 (0.59-0.96) P nominal = NS Immature (24% events) 2-year OS: 76.3% vs 74.0% BRCA status was post hoc PFS2 NR vs 18.4 months 0.5 (0.34-0.72)
NOVA Study Design (2016) Progression 6 months from last dose No measurable disease >2 cm; normal CA-125 or >90% decrease during last regimen (stable 7 days); PR or CR next to last/last platinum regimen Pre-Study Events Penultimate treatment course with a platinum-containing regimen Last treatment course with a platinumcontaining regimen Patient can be considered for the study and consented Study Events Non-gBRCA mut : sbrca mut, HRD+, HRD- Randomize patient within 8 wk of platinum-containing regimen based on centralized BRCA testing gbrca mut (n = 180) 2:1 Niraparib Placebo Disease progression: off study treatment Subsequent treatments Survival PRO/ imaging PRO Non-gBRCA mut (n = 289) 2:1 Niraparib Placebo Disease progression: off study treatment Subsequent treatments Survival National Institutes of Health, Available at: https://clinicaltrials.gov/ct2/show/nct01847274. Accessed October 12, 2017.
Platinum-Sensitive Relapse RCTs Maintenance After Chemotherapy: Niraparib (2017) Study Population N PFI, % Best platinum response, % 6-12 12+ CR PR gbrca 203 40 60 51 49 NOVA Non-gBRCA (sbrca, HRD- MyChoice wild type) 350 38 62 51 49 Study Population PFS PFS Other OS Notes NOVA gbrca Non-gBRCA (sbrca, HRD- MyChoice wild type) PFI, platinum-free interval; BICR, blinded independent central review BICR (I ) 21 vs 5.5 months 0.27 (0.17-0.41) BICR (I ) 9.3 vs 3.9 months 0.45 (0.34-0.61) HRD+ (sbrca/hrd) 12.9 vs 3.8 months 0.38 (0.24-0.59) Not yet mature Not yet mature Prior BEV: 25% HRD- only 6.9 vs 3.8 months 0.58 (0.36-0.92) Mahner S, et al. Presented at: Society of Gynecologic Oncology Annual Meeting on Women s Cancer; March 12-15, 2017: National Harbor, Maryland.
NOVA-Niraparib: PFS (2017) gbrca mut Non-gBRCA mut Overall Non-gBRCA mut HRD+ 100 Niraparib Placebo 100 Niraparib Placebo 100 Niraparib Placebo 75 75 75 PFS, % 50 PFS, % 50 PFS, % 50 25 25 25 0 0 2 4 6 8 10 12 14 16 18 20 22 24 0 0 2 4 6 8 10 12 14 16 18 20 22 24 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Time Since Randomization, mo Time Since Randomization, mo Time Since Randomization, mo HR 0.27, P<.0001 Median PFS, months Niraparib: 21.0 Placebo: 5.5 HR 0.45, P<.0001 Median PFS, months Niraparib: 9.3 Placebo: 3.9 HR 0.38, P<.0001 Median PFS, months Niraparib: 12.9 Placebo: 3.8 Mirza MR, et al. N Engl J Med. 2016;375:2154-2164.
First Approval of Switch Maintenance : Niraparib FDA approves maintenance treatment for recurrent epithelial ovarian, fallopian tube or primary peritoneal cancers [news release]. Silver Spring, MD: US Food & Drug Administration; March 27, 2017.
ARIEL3: Study Design Patient eligibility High-grade serous or endometrioid epithelial ovarian cancer, primary peritoneal, or fallopian tube cancers 2 prior lines of platinum-based treatments No prior PARP inhibitors Sensitive to penultimate platinum Responding to most recent platinum (CR or PR)* Excludes patients without assessable disease following surgery before more recent platinumbased therapy ECOG PS 1 CA-125 within normal range No restriction on size of residual tumor Randomisation 2:1 Stratification HRR status by NGS mutation analysis Mutation in BRCA1, BRCA2, or non-brca HRR gene No mutation in BRCA or HRR gene Response to recent platinum CR PR Progression-free interval after penultimate platinum 6 to <12 months 12 months Rucaparib 600 mg BID n = 375 Placebo BID n = 189 *CR (defined by RECIST v1.1) or PR (defined by RECIST v1.1 and/or a GCIG CA-125 response [CA-125 within normal range]) maintained until entry to ARIEL3 ( 8 weeks of last dose of chemotherapy). ATM, ATR, ATRX, BARD1, BLM, BRIP1, CHEK1, CHEK2, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, MRE11A, NBN, PALB2, RAD50, RAD51, RAD51B, RAD51C, RAD51D, RAD52, RAD54L, RPA1. HRR, homologous recombination repair; NGS, nextgeneration sequencing. Coleman RL, et al. Lancet. 2017 Sept 12. [Epub ahead of print]
ARIEL3: Primary Endpoint and Step-Down Analysis Primary endpoint: Investigator-assessed PFS (per RECIST) BRCA mutant Germline or somatic BRCA mutation If significant* HRD Germline or somatic BRCA mutation + BRCA wild type/loh high ( 16% genomic LOH prespecified) BRCA mutation and LOH in tumor samples were measured using an NGS assay If significant* Intent to treat (ITT) (all comers) Germline or somatic BRCA mutation + BRCA wild type/loh high + BRCA wild type/loh low + BRCA wild type/ LOH indeterminate *Investigator-assessed PFS at a two-sided 0.05 significance level Visit cutoff date for all analyses: April 15, 2017 Coleman RL, et al. Lancet. 2017 Sept 12. [Epub ahead of print]
ARIEL3: Investigator-Assessed PFS BRCA mutant ITT HRD Rucaparib (n = 130) Placebo (n = 66) Median (months) 95% CI 16.6 13.4-22.9 5.4 3.4-6.7 HR, 0.23; 95% CI, 0.16-0.34; P<.0001 Rucaparib (n = 375) Placebo (n = 189) Median (months) 95% CI 10.8 8.3-11.4 5.4 5.3-5.5 HR, 0.36; 95% CI, 0.30-0.45; P<.0001 Rucaparib (n = 236) Placebo (n = 118) Median (months) 95% CI 13.6 10.9-16.2 5.4 5.1-5.6 HR, 0.32; 95% CI, 0.24-0.42; P<.0001 At risk (events) Rucaparib 130 (0) 93 (23) 63 (46) 35 (58) 15 (64) 3 (67) 0 (67) Placebo 66 (0) 24 (37) 6 (53) 3 (55) 1 (56) 0 (56) Rucaparib, 48% censored Placebo, 15% censored At risk (events) Rucaparib 375 (0) 228 (111) 128 (186) 65 (217) 26 (226) 5 (234) 0 (234) Placebo 189 (0) 63 (114) 13 (160) 7 (164) 2 (167) 1 (167) 0 (167) Rucaparib, 38% censored Placebo, 12% censored At risk (events) Rucaparib 236 (0) 161 (55) 96 (104) 54 (122) 21 (129) 5 (134) 0 (134) Placebo 118 (0) 40 (68) 11 (95) 6 (98) 1 (101) 0 (101) Rucaparib, 43% censored Placebo, 14% censored Visit cutoff date: 15 April 2017 Coleman RL, et al. Lancet. 2017 Sept 12. [Epub ahead of print]
ARIEL3: Exploratory Analysis: Investigator-Assessed ORR for Patients With Measurable Disease at Baseline BRCA mutant HRD ITT Rucaparib (n = 40) Placebo (n = 23) Rucaparib (n = 85) Placebo (n = 41) Rucaparib (n = 141) Placebo (n = 66) RECIST ORR, % (n) 37.5* (15) 8.7 (2) 27.1* (23) 7.3 (3) 18.4* (26) 7.6 (5) Complete response 17.5 (7) 0 (0) 11.8 (10) 0 (0) 7.1 (10) 1.5 (1) Partial response 20.0 (8) 8.7 (2) 15.3 (13) 7.3 (3) 11.3 (16) 6.1 (4) Stable disease 47.5 (19) 34.8 (8) 50.6 (43) 41.5 (17) 50.4 (71) 43.9 (29) Progressive disease 12.5 (5) 56.5 (13) 21.2 (18) 51.2 (21) 27.0 (38) 48.5 (32) Not evaluable 2.5 (1) 0 (0) 1.2 (1) 0 (0) 4.3 (6) 0 (0) *Cochran-Mantel-Haenszel P<.05 vs placebo Visit cutoff date: 15 April 2017 Coleman RL, et al. Lancet. 2017 Sept 12. [Epub ahead of print]
Summary: Switch Maintenance Phase IIIs PFS (investigator review primary) Rucaparib Placebo HR P tbrca 16.8 5.4 0.23 P<.0001 tbrca + HRD 13.6 5.4 0.32 P<.0001 ITT 10.8 5.4 0.37 P<.0001 PFS (BICR primary) Niraparib Placebo HR P tbrca 21.0 5.5 0.26 P<.0001 tbrca + HRD NA NA NA All non-gbrca (sbrca + HRD + HRC) 9.3 3.9 0.45 P<.001 ITT (FDA analysis) 11.3 4.7 0.42 Not given PFS (investigator review - primary) Olaparib Placebo HR P gbrca 19.1 5.5 0.30 P<.0001
The New Treatment Landscape in Advanced Ovarian Cancer Progression Death Diagnosis GOG 218 ICON7 NOVA SOLO-2; Study 19 ARIEL3 Symptoms IV Carboplatin + Paclitaxel + Bevacizumab Bevacizumab Maintenance Platinum Doublet PARPi Maintenance Staging Other Lines of Therapy and Clinical Trials Progression-Free Survival (12-28 months) Post Progression Survival (12-38 months)
Antiangiogenesis and PARP Inhibition: Rationale Chronic hypoxia induces downregulation of BRCA1 and RAD51, and decreases homologous recombination in cancer cells Anti-VEGF induces hypoxia in the tumor microenvironment, which contributes to genomic instability and increased sensitivity of cells to PARP inhibition Combination With VEGF Inhibitor Cediranib/Olaparib Significantly Increased PFS Compared to Olaparib Alone in Platinum-Sensitive Recurrent Ovarian Cancer Olaparib Cediranib/ olaparib PFS events 28 19 Median PFS 9.0 months 17.7 months P =.005 HR 0.42 (95% CI: 0.23-0.76) Tentori L, et al. Eur J Cancer. 2007;43(14):2124-2133. Liu J, et al. Lancet Oncol. 2014;15(11):1207-1214.
Combination With VEGF Inhibitor (US, Canada, Japan, Korea) NRG GY004 (NCT02446600) Olaparib vs Olaparib-Cediranib vs PCT Recurrent HGSC with PFI > 6 months (following most recent platinum) No more than 3 prior regimens (including primary therapy) RECIST measurable or evaluable disease with accessible tumor No prior PARPi therapy, prior bevacizumab permitted Stratify for BRCA status, number of prior treatment regimens Primary endpoint: PFS 85% power with HR 0.625 Olaparib 300 mg BID R Cediranib 30 mg QD Olaparib 200 mg BID Open: FEB 2016 Status: Ongoing Accrual Target: 550 patients (135 BRCA1/2 +) Notes: Anticipate closure NOV2017 PCT, platinum-based chemotherapy Platinum-based combo* (IV) *Carboplatin + gemcitabine or paclitaxel or PLD Liu J, for NRG Oncology
Combination With VEGF Inhibitor (US, Canada) NRG GY005 (NCT02502266) Olaparib-Cediranib vs PCT Recurrent HGSC with PFI < 6 months (following most recent platinum) No more than 2 prior regimens (including primary therapy) RECIST measurable or evaluable disease, biopsy accessible No prior PARPi therapy, prior bevacizumab permitted Stratify for BRCA status, number of prior treatment regimens Primary endpoint: OS 90% power with HR 0.62 Phase II (n = 180) R Cediranib (PO) Olaparib (PO) Cediranib + olaparib (PO) Non-platinum chemo* (IV) Phase III (n = 280) R 1:1 Selected regimen (PO) Non-platinum chemo* (IV) * Weekly paclitaxel or PLD Open: FEB 2016 Status: Suspended for phase II interim analysis Target: 460 pts (135 BRCA1/2 +) Notes: Anticipate re-activation MAY2018 Lee J-M, for NRG Oncology
PAOLA-1 Study Design (NCT02477644) ARCAGY/GINECO Group sponsored study Combination With VEGF Inhibitor Phase III, randomized, double-blind, placebo-controlled, ex-us, multicenter study (maintenance setting) FIGO IIIb-IV High-grade serous or endometrioid, or epithelial nonmucinous ovarian, primary peritoneal, or fallopian tube cancer gbrcam Post 1 st line surgery and chemotherapy PR/CR 3 bevacizumab cycles N = 762 Randomization 2:1 Olaparib 300 mg tablets BID + bevacizumab 15 mg/kg Placebo tablets BID + bevacizumab 15 mg/kg Progression (up to 15 months) Follow up Primary endpoints Progression-free survival (up to 15 months) Key secondary endpoints Overall survival Time to earliest progression Second progression-free survival Time to first subsequent therapy or death Time to second subsequent therapy or death National Institutes of Health. Available at: http://www.clinicaltrials.gov/show/nct02477644.
Rationale for PARPi With Immune Checkpoint Inhibitors Combination With IO Hypermutable states BRCA-mutant (somatic/germline) have high intrinsic LOH High-grade serous ovarian cancer has a hypermutable genotype in a proportion of patients PARPi can induce a hypermutable state All increase potential for neoantigens potentially amenable to PD-1/L1 targeting PARPi synergy may vary by PARPi and checkpoint inhibitor
PARPi Plus Checkpoint Inhibitors (in Maintenance) Combination With IO 1. Pfizer (avelumab and talazoparib) 2. AstraZeneca (olaparib and durvalumab) 3. Tesaro (niraparib and TSR-042) 4. AstraZeneca (olaparib) and Merck (pembrolizumab) partnership (July 27, 2017) 5. Clovis (rucaparib) and Bristol-Myers Squibb (nivolumab) partnership (July 31, 2017)
Summary and Conclusions 1. PARPi are a new therapeutic class of agents in treating ovarian cancer 2. Options for treatment AND switch maintenance 3. Biomarkers are key to patient selection and sequencing BRCA (molecular) HRD/LOA (molecular) Response to platinum (clinical) 4. Key challenges include the development of rational combinations
Thank You bradley.monk@usoncology.com
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