Unanswered Questions in Primary Treatment of Ovarian Cancer: Controversial Areas Deborah K. Armstrong, M.D. May 29, 2009

Initial Therapy of Ovarian Cancer: Controversial Areas How can we best use targeted biologics with initial chemotherapy improve outcome?How can we best use targeted biologics with initial chemotherapy improve outcome? Should consolidation therapy be offered to all ovarian cancer patients?Should consolidation therapy be offered to all ovarian cancer patients? –Does receiving consolidation therapy alter response to subsequent chemotherapy? Should BRCA-associated cancers be treated differently?Should BRCA-associated cancers be treated differently? Should cost of treatment be an issue in designing clinical trials?Should cost of treatment be an issue in designing clinical trials? Should access/eligibility be broadened to reflect the “real world”Should access/eligibility be broadened to reflect the “real world”

Initial Therapy of Ovarian Cancer: Controversial Areas How can we best use targeted biologics with initial chemotherapy improve outcome?How can we best use targeted biologics with initial chemotherapy improve outcome? Should consolidation therapy be offered to all ovarian cancer patients?Should consolidation therapy be offered to all ovarian cancer patients? –Does receiving consolidation therapy alter response to subsequent chemotherapy? Should BRCA-associated cancers be treated differently?Should BRCA-associated cancers be treated differently? Should cost of treatment be an issue in designing clinical trials?Should cost of treatment be an issue in designing clinical trials? Should access/eligibility be broadened to reflect the “real world”Should access/eligibility be broadened to reflect the “real world”

Models for addition of targeted biologic therapy to initial chemotherapy Concurrent Chemo & Biologic Concurrent Chemo & Biologic with Maintenance/Consolidation Sequential Chemo followed by Biologic (as Maintenance/Consolidation) Biologic AgentChemotherapy

GOG 218 OvCaIII/IVSubopt Paclitaxel 175 mg/m 2 /3h Carboplatin AUC = 6 q 21 d x 6 Bev d1 X 5 begin cycle 2 Paclitaxel 175 mg/m 2 /3h Carboplatin AUC = 6 q 21 d x 6 Placebo d1 X 5 begin cycle 2 Paclitaxel 175 mg/m 2 /3h Carboplatin AUC = 6 q 21 d x 6 Bev d1 X 5 begin cycle 2 RANDOMIZE Burger, R. GOG 218 Placebo q 21d X 15 mos Placebo q 21d X 15 mos Bev q 21d X 15 mos Bevacizumab 15 mg/kg IV

ICON 7 (Front-line European Trial) Stages I-IV ovarian and peritoneal cancer –Stratified according to stage, optimal status region or country Carboplatin AUC 6 plus paclitaxel 175 mg/m 2 (3 hr) q 21d x 6 RANDOMIZERANDOMIZE Carboplatin AUC 6 plus paclitaxel 175 mg/m 2 (3 hr) q 21d x 6 plus bevacizumab at 7.5 mg/kg followed by bevacizumab at 7.5 mg/kg q 21 d x 12 months Accrual goal: 1,444 patients Primary endpoint: PFS Other endpoints: OS (10 mo), RR, Toxicity Translational Research Tissue and serum markers of angiogenesis Genomics DCE-MRI Quality of life Health economics DCE-MRI = dynamic contrast-enhanced magnetic resonance imaging ICON = International Collaborative Ovarian Neoplasm Group OS = overall response RR = response rate

RA N D O M I S E Observation Tarceva 150 mg daily for up to 2 years or until PD Stage Ic to IV epith. ovarian cancer, having achieved CR/PR/SD on platinum-based chemo (6-9 courses) N = 830 Endpoints: PFS and overall survival Recruitment completed, study ongoing FIRST LINE MAINTENANCE (EORTC) – WITH TRANSLATIONAL SUB-STUDY

Initial Therapy of Ovarian Cancer: Controversial Areas How can we best use targeted biologics with initial chemotherapy improve outcome?How can we best use targeted biologics with initial chemotherapy improve outcome? Should consolidation therapy be offered to all ovarian cancer patients?Should consolidation therapy be offered to all ovarian cancer patients? –Does receiving consolidation therapy alter response to subsequent chemotherapy? Should BRCA-associated cancers be treated differently?Should BRCA-associated cancers be treated differently? Should cost of treatment be an issue in designing clinical trials?Should cost of treatment be an issue in designing clinical trials? Should access/eligibility be broadened to reflect the “real world”Should access/eligibility be broadened to reflect the “real world”

GOG #178 SWOG #9701 Ovarian cancer Stage III or IV 5-6 cycles platinum and Paclitaxel, in Clinical CR RANDOMIZE Paclitaxel 135 mg/m2/3h Q 28 days x 3 Paclitaxel 135 mg/m2/3h Q 28 days x 12

GOG #178 SWOG # months 3 months # pts at risk # relapsed 2034 Median PFS 28 months 21 months P=.0023

Overall Survival 0% 20% 40% 60% 80% 100% Months After Registration Paclitaxel 12 courses Paclitaxel 3 courses At Risk Deaths Median in Months SWOG 9701/GOG 178: Overall Survival Markman M, et al. J Clin Oncol. 2006;24(18S):Abstract 5005.

Initial Therapy of Ovarian Cancer: Controversial Areas How can we best use targeted biologics with initial chemotherapy improve outcome?How can we best use targeted biologics with initial chemotherapy improve outcome? Should consolidation therapy be offered to all ovarian cancer patients?Should consolidation therapy be offered to all ovarian cancer patients? –Does receiving consolidation therapy alter response to subsequent chemotherapy? Should BRCA-associated cancers be treated differently?Should BRCA-associated cancers be treated differently? Should cost of treatment be an issue in designing clinical trials?Should cost of treatment be an issue in designing clinical trials? Should access/eligibility be broadened to reflect the “real world”Should access/eligibility be broadened to reflect the “real world”

Initial Therapy of Ovarian Cancer: Controversial Areas How can we best use targeted biologics with initial chemotherapy improve outcome?How can we best use targeted biologics with initial chemotherapy improve outcome? Should consolidation therapy be offered to all ovarian cancer patients?Should consolidation therapy be offered to all ovarian cancer patients? –Does receiving consolidation therapy alter response to subsequent chemotherapy? Should BRCA-associated cancers be treated differently?Should BRCA-associated cancers be treated differently? Should cost of treatment be an issue in designing clinical trials?Should cost of treatment be an issue in designing clinical trials? Should access/eligibility be broadened to reflect the “real world”Should access/eligibility be broadened to reflect the “real world”

In response to DNA damage the Fanconi Anemia (FA) complex is activated, translocated and binds with chromatin containing the BRCA1 protein and BRCA2 proteins. This complex promotes DNA repair. In the presence of mutated, nonfunctional or absent BRCA1 or BRCA2 proteins, DNA repair is compromised increasing sensitivity to chemotherapeutic agents, particularly the platinum salts. Olopade and Wei, Cell 2003

Ovarian Cancer Relapse: Effect of BRCA Mutations Boyd et.el. JAMA 2000

Ovarian Cancer Survival: Effect of BRCA Mutations Cass et.al. Cancer May 2003

BRCA1 and BRCA2 Mutated Ovarian Carcinomas BRCA1 and BRCA2 are critical proteins in DNA repair via homologous recombination BRCA-associated cancers develop after a deletion or mutation of the wildtype allele Normal non-malignant cells retain the wildtype allele and intact BRCA function Cells defective in BRCA1 or BRCA2 are more sensitive to ionizing radiation and platinum compounds BRCA-deficient cells are dependent on an alternate, PARP-dependent DNA repair pathway

Questions about the use of PARP inhibitors in ovarian cancer Is there a role for PARP inhibitors in ovarian cancer patients without a BRCA mutation?Is there a role for PARP inhibitors in ovarian cancer patients without a BRCA mutation? –Other defects in the homologous recombination pathway –BRCA promoter methylation to silence BRCA genes Will resistance develop to PARP inhibitors?Will resistance develop to PARP inhibitors? –Documentation of second BRCA mutations that revert to wild type function Are platinum resistant patients likely to be PARP inhibition resistant?Are platinum resistant patients likely to be PARP inhibition resistant?

Initial Therapy of Ovarian Cancer: Controversial Areas How can we best use targeted biologics with initial chemotherapy improve outcome?How can we best use targeted biologics with initial chemotherapy improve outcome? Should consolidation therapy be offered to all ovarian cancer patients?Should consolidation therapy be offered to all ovarian cancer patients? –Does receiving consolidation therapy alter response to subsequent chemotherapy? Should BRCA-associated cancers be treated differently?Should BRCA-associated cancers be treated differently? Should cost of treatment be an issue in designing clinical trials?Should cost of treatment be an issue in designing clinical trials? Should access/eligibility be broadened to reflect the “real world”Should access/eligibility be broadened to reflect the “real world”

Comparative Effectiveness $1.1 Billion of ARRA funds slated for comparative effectiveness research (CER)$1.1 Billion of ARRA funds slated for comparative effectiveness research (CER) No agreement on definition of CERNo agreement on definition of CER –Efficacy is determined within specific populations under controlled conditions –Effectiveness is closer to what actually happens in the real world “Cooperative groups, being publicly funded, may be best positioned to conduct such studies”“Cooperative groups, being publicly funded, may be best positioned to conduct such studies” The CER agenda may conflict with the mission to advance scienceThe CER agenda may conflict with the mission to advance science The Cancer Letter, May 22, 2009

From Edmonson, Gynecologic Oncology, 2000