Unanswered Questions in Primary Treatment of Ovarian Cancer: Controversial Areas

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

2. Initial Therapy of Ovarian Cancer: Controversial Areas • How can we best use targeted biologics with initial chemotherapy improve outcome? • 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 cost of treatment be an issue in designing clinical trials? • Should access/eligibility be broadened to reflect the “real world”

3. Initial Therapy of Ovarian Cancer: Controversial Areas • How can we best use targeted biologics with initial chemotherapy improve outcome? • 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 cost of treatment be an issue in designing clinical trials? • Should access/eligibility be broadened to reflect the “real world”

4. 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) Chemotherapy Biologic Agent

5. GOG 218 Paclitaxel 175 mg/m2/3h Carboplatin AUC = 6 q 21 d x 6 Placebo d1 X 5 begin cycle 2 Placebo q 21d X 15 mos R A N D O M I Z E OvCa III/IV Subopt Paclitaxel 175 mg/m2/3h Carboplatin AUC = 6 q 21 d x 6 Bev d1 X 5 begin cycle 2 Placebo q 21d X 15 mos Paclitaxel 175 mg/m2/3h Carboplatin AUC = 6 q 21 d x 6 Bev d1 X 5 begin cycle 2 Bev q 21d X 15 mos Burger, R. GOG 218 Bevacizumab 15 mg/kg IV

6. ICON 7 (Front-line European Trial) Stages I-IV ovarian and peritoneal cancer Stratified according to stage, optimal status region or country R A N D O M I Z E Carboplatin AUC 6 plus paclitaxel 175 mg/m2 (3 hr) q 21d x 6 Carboplatin AUC 6 plus paclitaxel 175 mg/m2 (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 • Translational Research • Tissue and serum markers of angiogenesis • Genomics • DCE-MRI • Quality of life • Health economics Accrual goal: 1,444 patients Primary endpoint: PFS Other endpoints: OS (10 mo), RR, Toxicity DCE-MRI = dynamic contrast-enhanced magnetic resonance imaging ICON = International Collaborative Ovarian Neoplasm Group OS = overall response RR = response rate

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

8. Initial Therapy of Ovarian Cancer: Controversial Areas • How can we best use targeted biologics with initial chemotherapy improve outcome? • 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 cost of treatment be an issue in designing clinical trials? • Should access/eligibility be broadened to reflect the “real world”

9. GOG #178SWOG #9701 Paclitaxel 135 mg/m2/3h Q 28 days x 3 R A N D O M I Z E Ovarian cancer Stage III or IV 5-6 cycles platinum and Paclitaxel, in Clinical CR Paclitaxel 135 mg/m2/3h Q 28 days x 12

10. GOG #178SWOG #9701

11. SWOG 9701/GOG 178:Overall Survival Overall Survival 100% 80% 60% 40% 20% Median At Risk Deaths in Months Paclitaxel 12 courses 150 66 53 Paclitaxel 3 courses 146 80 46 0% 0 24 48 72 96 Months After Registration Markman M, et al. J Clin Oncol. 2006;24(18S):Abstract 5005.

12. Initial Therapy of Ovarian Cancer: Controversial Areas • How can we best use targeted biologics with initial chemotherapy improve outcome? • 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 cost of treatment be an issue in designing clinical trials? • Should access/eligibility be broadened to reflect the “real world”

13. Initial Therapy of Ovarian Cancer: Controversial Areas • How can we best use targeted biologics with initial chemotherapy improve outcome? • 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 cost of treatment be an issue in designing clinical trials? • Should access/eligibility be broadened to reflect the “real world”

14. 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

15. Ovarian Cancer Relapse:Effect of BRCA MutationsBoyd et.el. JAMA 2000

16. Ovarian Cancer Survival:Effect of BRCA MutationsCass et.al. Cancer May 2003

17. 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

18. 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? • Other defects in the homologous recombination pathway • BRCA promoter methylation to silence BRCA genes • 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?

19. Initial Therapy of Ovarian Cancer: Controversial Areas • How can we best use targeted biologics with initial chemotherapy improve outcome? • 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 cost of treatment be an issue in designing clinical trials? • Should access/eligibility be broadened to reflect the “real world”

20. Comparative Effectiveness • $1.1 Billion of ARRA funds slated for comparative effectiveness research (CER) • No 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” • The CER agenda may conflict with the mission to advance science The Cancer Letter, May 22, 2009

21. From Edmonson, Gynecologic Oncology , 2000