Maintenance Therapy for Ovarian Cancer – Do the Benefits Outweigh the Risks? Bradley J. Monk, MD, FACS, FACOG Professor and Director Division of Gynecologic Oncology Department of Obstetrics and Gynecology Creighton University School of Medicine at St. Joseph’s Hospital and Medical Center, a Dignity Health Member University of Arizona Cancer Center-Phoenix Arizona USA [email protected]
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Maintenance Therapy for Ovarian Cancer – Do the Benefits Outweigh the Risks?
Maintenance Therapy for Ovarian Cancer – Do the Benefits Outweigh the Risks?. Bradley J. Monk, MD, FACS, FACOG Professor and Director Division of Gynecologic Oncology Department of Obstetrics and Gynecology - PowerPoint PPT Presentation
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Maintenance Therapy for Ovarian Cancer – Do the Benefits Outweigh the Risks?
Bradley J. Monk, MD, FACS, FACOGProfessor and Director
Division of Gynecologic OncologyDepartment of Obstetrics and GynecologyCreighton University School of Medicine atSt. Joseph’s Hospital and Medical Center,
a Dignity Health MemberUniversity of Arizona Cancer Center-Phoenix Arizona USA
What we know…•Rate of response is high (CR + PR) >75%•Second assessment operations find disease > 40% of CR’s•Clinical CR’s have >50% recurrence risk at 2 years•Pathological CR’s have >40% risk at 2 years•Option applies to CR’s and documented PR’s
Maintenance Strategies inEpithelial Ovarian Cancer
NEJM Data cut-off date August 26, 2011(ASCO 2010 cut-off date February 5, 2010)Randall LM et al SGO 2013
1111
ICON7: a phase III Gynaecologic Cancer InterGroup (GCIG) trial of adding bevacizumab
to standard chemotherapy in women with newly diagnosed epithelial ovarian, primary peritoneal
or fallopian tube cancerTim Perren, Ann Marie Swart, Jacobus Pfisterer, Jonathan Tim Perren, Ann Marie Swart, Jacobus Pfisterer, Jonathan
Ledermann, Alain Lortholary, Gunnar Kristensen, Mark Carey, Ledermann, Alain Lortholary, Gunnar Kristensen, Mark Carey, Philip Beale, Andreas Cervantes, Amit Oza Philip Beale, Andreas Cervantes, Amit Oza
on behalf of GCIG ICON7 collaborators on behalf of GCIG ICON7 collaborators (MRC/NCRI, AGO-OVAR, GINECO, NSGO, ANZGOG, (MRC/NCRI, AGO-OVAR, GINECO, NSGO, ANZGOG,
GEICO, NCIC-CTG)GEICO, NCIC-CTG)ESMOESMO
2010 N Engl J Med. 2011 Dec 29;365(26):2484-96.2010 N Engl J Med. 2011 Dec 29;365(26):2484-96.
ICON7: Study Design
Stratification variables: Stratification variables: • Stage/surgeryStage/surgery• Time since surgeryTime since surgery• GCIG groupGCIG group *Might vary based on GCIG group*Might vary based on GCIG group
****Omit cycle 1 bevacizumab if <4 weeks from surgeryOmit cycle 1 bevacizumab if <4 weeks from surgery
Paclitaxel 175 mg/mPaclitaxel 175 mg/m22
Carboplatin AUC Carboplatin AUC 6*6*
AVASTINAVASTIN
Carboplatin AUC 6*Carboplatin AUC 6*
Paclitaxel 175 mg/mPaclitaxel 175 mg/m22
Arm A
Arm A
ArmArm BB
12 months12 months
Front-line EOC, Front-line EOC, PP or FT cancerPP or FT cancer
• Stage I-IIA (Gr 3 Stage I-IIA (Gr 3 or CC) or CC)
• Stage IIB/CStage IIB/C• Stage IIIStage III• Stage IVStage IV
Exploratory Exploratory endpoints:endpoints:IRC, CA 125 IRC, CA 125 response, ascitesresponse, ascites
IRC presentIRC present
ClinicalTrials.gov Identifier: NCT00434642 Aghajanian C et al J Clin Oncol 29: 2011 (suppl; abstr LBA5007)
242242 177177 4545 1111 33 00CG + PLCG + PL
OCEANS: Primary analysis of PFSCG + PL(n=242)
CG + BV(n=242)
Events, n (%) 187 (77) 151 (62)
Median PFS, months (95% CI)
8.4(8.3–9.7)
12.4(11.4–12.7)
Stratified analysis HR (95% CI)Log-rank p-value
0.484 (0.388–0.605)
<0.0001
MonthsMonthsNo. at riskNo. at risk
242242 203203 9292 3333 1111 00CG + BVCG + BV
1.0
0.8
0.6
0.4
0.2
0
1.0
0.8
0.6
0.4
0.2
0
Pro
po
rtio
n p
rog
res
sio
n f
ree
Pro
po
rtio
n p
rog
res
sio
n f
ree
00 66 1212 1818 2424 3030
ASCO 2011Aghajanian C et al J Clin Oncol 29: 2011 (suppl; abstr LBA5007)
1.0
Prop
ortio
n su
rviv
ing
OCEANS: OS Analyses
aData cutoff date: Sept 17, 2010. Median follow-up of 24 months in both arms, with 141 deaths (29% of patients). bData cutoff date: Aug 29, 2011. Median follow-up 33.7 months in PL arm and 35.4 months in BV arm, with 235 deaths (49% of patients).
GC + PL(n=242)
GC + BV(n=242)
No. events (%) 78 (32.2) 63 (26.0)Median OS, mo 29.9 35.5HR (95% CI) 0.751 (0.537–1.052)Log-rank P value .0944
GC + PL (n=242)
GC + BV(n=242)
No. events (%) 112 (46.3) 123 (50.8)Median OS, mo 35.2 33.3HR (95% CI) 1.027 (0.792–1.331)Log-rank P value .8422
0 6 12 18 24 30 36 42
Months
1.0
0.8
0.6
0.4
0.2
0.0
Prop
ortio
n su
rviv
ing
GC + PL(n=242)
GC + BV(n=242)
First Interim AnalysisaSecond Interim Analysisb
0 6 12 18 24 30 36 42 48 54
Months
0.8
0.6
0.4
0.2
0.0
Maintenance Strategies inEpithelial Ovarian Cancer
N = 450 anticipatedAccrual closed 9/6/01N = 277; 222 with FU54 progression events
End points• PFS• OS
FU = follow-up.
Markman et al, J Clin Oncol 2003.
Unadjusted Log Rankp (1-sided) = .0035
Adjusted Log Rankp (1-sided) = .0023
Markman et al, J Clin Oncol 2003.
Maintenance Chemotherapy: GOG 178
GOG-0212Phase III Maintenance Therapy Trial
Primary endpoint: survivalSecondary endpoints: PFS, toxicity, QoL
OPEN TO PATIENT ENTRY MARCH, 2005
CLOSED TO ENROLLMENT JANUARY, 2014 www.clinicaltrials.gov/ct2/show/NCT00108745.
Macromolecular complexMacromolecular complex of paclitaxel poliglumexof paclitaxel poliglumex
Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin
( N = 1100)
Paclitaxel Every 28 days for up to 12 courses
No treatment
Paclitaxel poliglumex Every 28 days for up to 12 courses
Maintenance Strategies inEpithelial Ovarian Cancer
Courtesy of Robert Coleman, MD.Adapted from Coleman, 2009.
Even Wider Catch: BRCAness “Profile”
Konstantinopoulos PA, et al. J Clin Oncol. 2010;28:3555.
BRCAness and Response to Chemotherapy
Disease Free Survival Overall Survival
Konstantinopoulos PA, et al. J Clin Oncol. 2010;28:3555.
34 v 15 mo P = 0.01
72 v 41 mo P = 0.006
Phase II study of the oral PARP inhibitor olaparib (AZD2281) versus liposomal doxorubicin in ovarian
cancer patients with BRCA1 and/or BRCA2 mutations
Stan Kaye,Stan Kaye,11 Bella Kaufman, Bella Kaufman,2 2 Jan Lubinski,Jan Lubinski,3 3
Ursula Matulonis,Ursula Matulonis,44 Charlie Gourley, Charlie Gourley,55 Beth Karlan, Beth Karlan,6 6
Dianna Taylor,Dianna Taylor,77 Mark Wickens, Mark Wickens,77 James Carmichael James Carmichael77
1. Royal Marsden Hospital, Sutton, Surrey, UK1. Royal Marsden Hospital, Sutton, Surrey, UK
2. Chaim Sheba Medical Center, Tel Hashomer, Israel 2. Chaim Sheba Medical Center, Tel Hashomer, Israel
3. Pomeranian Medical University, Szczecin, Poland3. Pomeranian Medical University, Szczecin, Poland
4. Dana-Farber Cancer Institute, Boston, MA, USA4. Dana-Farber Cancer Institute, Boston, MA, USA
5. University of Edinburgh Cancer Research Centre, Western General Hospital, Edinburgh, UK5. University of Edinburgh Cancer Research Centre, Western General Hospital, Edinburgh, UK
6. Cedars-Sinai Medical Center, Los Angeles, CA, USA6. Cedars-Sinai Medical Center, Los Angeles, CA, USA
7. AstraZeneca, Alderley Park, Macclesfield, UK7. AstraZeneca, Alderley Park, Macclesfield, UK
Clinicaltrials.gov number, NCT00628251
ESMO 2010ESMO 2010
Kaye S, et al. Ann Oncol. 2010;21(suppl 8). Abstract 9710; J Clin Oncol. 2012 Feb 1;30(4):372-9.
Randomized
1:1:1
Olaparib 200 mg bid in 28-day cycles
PLD 50 mg/m2 IV every 4 weeks
PD or withdrawal from treatment for
other reason
As above or max lifetime cumulative
dose reached
Primary objective: Compare efficacy (PFS) of 2 dose levels of olaparib (200 mg and 400 mg bid) with pegylated liposomal doxorubicin (PLD)
Study Design
Olaparib 400 mg bid in 28-day cycles
BRCA1/2 germline carriers with Ovarian CaProgressive or recurrent disease < 12 months after previous platinum-based chemotherapy
Patients in PLD group were allowed to cross over to olaparib 400 mg bid on confirmed PD
Stats: HR 0.55 (median PFS of 4 to 7.3 mos)N planned: 90 (30/arm)
Kaye S, et al. Ann Oncol. 2010;21(suppl 8). Abstract 9710; J Clin Oncol. 2012 Feb 1;30(4):372-9.
BRCAwt, wild type (includes patients with no known BRCAm or a mutation of unknown significance)
Presented by: Jonathan Ledermann et al at ASCO 2013
Study 19:Time to second subsequent therapy (PFS2)
• ORR post-olaparib = 36% (24/67) by RECIST
Platinum = 40% (19/48) by RECIST
• ORR post-olaparib = 45% (35/78) by RECIST + GCIG
• No evidence of secondary BRCA1/2 mutations detected in tumor samples of 6 PARPi-resistant patients
Front-Line Olaparib Maintenance Therapy
A Phase III, Randomised, Double Blind, Placebo Controlled, Multicentre Study of Olaparib Maintenance Monotherapy in Patients with BRCA Mutated Advanced (FIGO Stage III-IV)
Ovarian Cancer following First Line Platinum Based Chemotherapy
(GOG 3004)
ClinicalTrials.gov (identifier: NCT01844986
Olaparib Maintenance Therapy in Platinum Sensitive Ovarian Cancer
A Phase III, Randomized, Double Blind, Placebo Controlled, Multicenter Study of Olaparib Maintenance Monotherapy in Patients with BRCA Mutated Relapsed
Ovarian Cancer Following Complete or Partial Response Following Platinum Based Chemotherapy:
SOLO-2
ClinicalTrials.gov (identifier: NCT01874353
PARPi in Phase III Development in Ovarian Cancer
1. AZD 2281 (KU-0059436) = Olaparib
2. MK-4827 = Niraparib
3. CO-338 (AG014699, PF-01367338) = Rucaparib
Niraparib: Phase 1/2 Ovarian Cancer Anti-tumor Activity
RECIST response rate in platinum-sensitive patients was 46% (6/13) Response rate (by RECIST and/or GCIG Ca125 criteria) in evaluable platinum-
resistant patients was 22% (6/27)
* BRCA1/2 mutation carriers † Reduction in overall sum of measurable disease but new lesion seen (overall: PD)-Refractory patient (BRCA mutated) not included