Unanswered Questions Unanswered Questions in Primary Treatment in Primary Treatment of Ovarian Cancer: of Ovarian Cancer: Controversial AreasControversial Areas

Deborah K. Armstrong, M.D.Deborah K. Armstrong, M.D.May 29, 2009May 29, 2009

Initial Therapy of Ovarian Cancer:Initial Therapy of Ovarian Cancer: Controversial Areas Controversial Areas

• How can we best use targeted biologics with initial How can we best use targeted biologics with initial chemotherapy improve outcome?chemotherapy improve outcome?

• Should consolidation therapy be offered to all ovarian Should consolidation therapy be offered to all ovarian cancer patients?cancer patients?– Does receiving consolidation therapy alter response Does receiving consolidation therapy alter response

to subsequent chemotherapy?to subsequent chemotherapy?• Should BRCA-associated cancers be treated Should BRCA-associated cancers be treated

differently?differently?• Should cost of treatment be an issue in designing Should cost of treatment be an issue in designing

clinical trials?clinical trials?• Should access/eligibility be broadened to reflect the Should access/eligibility be broadened to reflect the

“real world”“real world”

Initial Therapy of Ovarian Cancer:Initial Therapy of Ovarian Cancer: Controversial Areas Controversial Areas

• How can we best use targeted biologics with initial How can we best use targeted biologics with initial chemotherapy improve outcome?chemotherapy improve outcome?

• Should consolidation therapy be offered to all ovarian Should consolidation therapy be offered to all ovarian cancer patients?cancer patients?– Does receiving consolidation therapy alter response Does receiving consolidation therapy alter response

to subsequent chemotherapy?to subsequent chemotherapy?• Should BRCA-associated cancers be treated Should BRCA-associated cancers be treated

differently?differently?• Should cost of treatment be an issue in designing Should cost of treatment be an issue in designing

clinical trials?clinical trials?• Should access/eligibility be broadened to reflect the Should access/eligibility be broadened to reflect the

“real world”“real world”

Models for addition of targeted biologic Models for addition of targeted biologic therapy to initial chemotherapytherapy to initial chemotherapy

Concurrent Chemo & Biologic

Concurrent Chemo & Biologic with Maintenance/Consolidation

Sequential Chemo followed by Biologic (as Maintenance/Consolidation)

Biologic AgentChemotherapy

GOG 218GOG 218

OvCa OvCa III/IVIII/IVSuboptSubopt

Paclitaxel Paclitaxel 175 mg/m175 mg/m22/3h/3hCarboplatinCarboplatin AUC = 6 AUC = 6

q 21 d x 6q 21 d x 6BevBev d1 X 5 d1 X 5

begin cycle 2begin cycle 2

Paclitaxel Paclitaxel 175 mg/m175 mg/m22/3h/3hCarboplatinCarboplatin AUC = 6 AUC = 6

q 21 d x 6q 21 d x 6PlaceboPlacebo d1 X 5 d1 X 5begin cycle 2begin cycle 2

Paclitaxel Paclitaxel 175 mg/m175 mg/m22/3h/3hCarboplatinCarboplatin AUC = 6 AUC = 6

q 21 d x 6q 21 d x 6BevBev d1 X 5 d1 X 5

begin cycle 2begin cycle 2

RRAANNDDOOMMIIZZEE

Burger, R. GOG 218 Burger, R. GOG 218

Placebo

q 21d X 15 mos

Placebo

q 21d X 15 mosBev

q 21d X 15 mos

Bevacizumab 15 mg/kg IV

ICON 7 (Front-line European Trial)ICON 7 (Front-line European Trial)

Stages I-IV ovarian and Stages I-IV ovarian and peritoneal cancerperitoneal cancer

– Stratified according to Stratified according to stage, optimal status stage, optimal status region or countryregion or country

Carboplatin AUC 6 pluspaclitaxel 175 mg/m2 (3 hr) q 21d x 6

RANDOMIZE

Carboplatin AUC 6 pluspaclitaxel 175 mg/m2 (3 hr) q 21d x 6plus bevacizumab at 7.5 mg/kgfollowed by bevacizumab at 7.5 mg/kgq 21 d x 12 months

Accrual goal: 1,444 patientsPrimary endpoint: PFSOther 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 GroupOS = overall responseRR = response rate

DCE-MRI = dynamic contrast-enhanced magnetic resonance imaging ICON = International Collaborative Ovarian Neoplasm GroupOS = overall responseRR = response rate

RANDOM 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:Initial Therapy of Ovarian Cancer: Controversial Areas Controversial Areas

• How can we best use targeted biologics with initial How can we best use targeted biologics with initial chemotherapy improve outcome?chemotherapy improve outcome?

• Should consolidation therapy be offered to all ovarian Should consolidation therapy be offered to all ovarian cancer patients?cancer patients?– Does receiving consolidation therapy alter response Does receiving consolidation therapy alter response

to subsequent chemotherapy?to subsequent chemotherapy?• Should BRCA-associated cancers be treated Should BRCA-associated cancers be treated

differently?differently?• Should cost of treatment be an issue in designing Should cost of treatment be an issue in designing

clinical trials?clinical trials?• Should access/eligibility be broadened to reflect the Should access/eligibility be broadened to reflect the

“real world”“real world”

GOG #178GOG #178SWOG #9701SWOG #9701

Ovarian cancerOvarian cancerStage III or IVStage III or IV5-6 cycles 5-6 cycles platinum and platinum and Paclitaxel, inPaclitaxel, inClinical CRClinical CR

RRAANNDDOOMMIIZZEE

Paclitaxel Paclitaxel 135 mg/m2/3h135 mg/m2/3hQ 28 days x Q 28 days x 33

Paclitaxel Paclitaxel 135 mg/m2/3h135 mg/m2/3hQ 28 days x Q 28 days x 1212

GOG #178GOG #178SWOG #9701SWOG #9701

12 months12 months 3 months3 months

# pts at risk# pts at risk 110110 112112

# relapsed# relapsed 2020 3434

Median PFSMedian PFS 28 months28 months 21 months21 months

P=.0023

Overall Survival

0%

20%

40%

60%

80%

100%

0 24 48 72 96Months After Registration

Paclitaxel 12 coursesPaclitaxel 3 courses

At Risk150146

Deaths6680

Medianin Months

5346

SWOG 9701/GOG 178:Overall Survival

Markman M, et al. J Clin Oncol. 2006;24(18S):Abstract 5005.

Initial Therapy of Ovarian Cancer:Initial Therapy of Ovarian Cancer: Controversial Areas Controversial Areas

• How can we best use targeted biologics with initial How can we best use targeted biologics with initial chemotherapy improve outcome?chemotherapy improve outcome?

• Should consolidation therapy be offered to all ovarian Should consolidation therapy be offered to all ovarian cancer patients?cancer patients?– Does receiving consolidation therapy alter response Does receiving consolidation therapy alter response

to subsequent chemotherapy?to subsequent chemotherapy?• Should BRCA-associated cancers be treated Should BRCA-associated cancers be treated

differently?differently?• Should cost of treatment be an issue in designing Should cost of treatment be an issue in designing

clinical trials?clinical trials?• Should access/eligibility be broadened to reflect the Should access/eligibility be broadened to reflect the

“real world”“real world”

Initial Therapy of Ovarian Cancer:Initial Therapy of Ovarian Cancer: Controversial Areas Controversial Areas

• How can we best use targeted biologics with initial How can we best use targeted biologics with initial chemotherapy improve outcome?chemotherapy improve outcome?

• Should consolidation therapy be offered to all ovarian Should consolidation therapy be offered to all ovarian cancer patients?cancer patients?– Does receiving consolidation therapy alter response Does receiving consolidation therapy alter response

to subsequent chemotherapy?to subsequent chemotherapy?• Should BRCA-associated cancers be treated Should BRCA-associated cancers be treated

differently?differently?• Should cost of treatment be an issue in designing Should cost of treatment be an issue in designing

clinical trials?clinical trials?• Should access/eligibility be broadened to reflect the Should access/eligibility be broadened to reflect the

“real world”“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 Questions about the use of PARP inhibitors in ovarian cancerPARP inhibitors in ovarian cancer

• Is there a role for PARP inhibitors in ovarian cancer Is there a role for PARP inhibitors in ovarian cancer patients without a BRCA mutation?patients without a BRCA mutation?– Other defects in the homologous recombination Other defects in the homologous recombination

pathwaypathway– BRCA promoter methylation to silence BRCA genes 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 Documentation of second BRCA mutations that

revert to wild type functionrevert to wild type function• Are platinum resistant patients likely to be PARP Are platinum resistant patients likely to be PARP

inhibition resistant?inhibition resistant?

Initial Therapy of Ovarian Cancer:Initial Therapy of Ovarian Cancer: Controversial Areas Controversial Areas

• How can we best use targeted biologics with initial How can we best use targeted biologics with initial chemotherapy improve outcome?chemotherapy improve outcome?

• Should consolidation therapy be offered to all ovarian Should consolidation therapy be offered to all ovarian cancer patients?cancer patients?– Does receiving consolidation therapy alter response Does receiving consolidation therapy alter response

to subsequent chemotherapy?to subsequent chemotherapy?• Should BRCA-associated cancers be treated Should BRCA-associated cancers be treated

differently?differently?• Should cost of treatment be an issue in designing Should cost of treatment be an issue in designing

clinical trials?clinical trials?• Should access/eligibility be broadened to reflect the Should access/eligibility be broadened to reflect the

“real world”“real world”

Comparative EffectivenessComparative Effectiveness• $1.1 Billion of ARRA funds slated for comparative $1.1 Billion of ARRA funds slated for comparative

effectiveness research (CER)effectiveness research (CER)• No agreement on definition of CERNo agreement on definition of CER

– Efficacy is determined within specific populations Efficacy is determined within specific populations under controlled conditionsunder controlled conditions

– Effectiveness is closer to what actually happens Effectiveness is closer to what actually happens in the real worldin the real world

• ““Cooperative groups, being publicly funded, may be Cooperative groups, being publicly funded, may be best positioned to conduct such studies”best positioned to conduct such studies”

• The CER agenda may conflict with the mission to The CER agenda may conflict with the mission to advance scienceadvance science

The Cancer Letter, May 22, 2009

From Edmonson, Gynecologic Oncology , 2000