PARP and Other DNA Damage Repair Inhibitors in Solid Tumors: An Update

Program Overview

Discussion Outline

DNA Repair

ABCs of DNA Repair

DNA Repair Defects in Cancer

DNA Repair Defects Can Be an Achilles' Heel

Synthetic Lethality and Cancer DNA Repair Defects

Increased Sensitivity of BRCA1-/- and BRCA2-/- Cells to PARP Inhibition

A Common Challenge for PARP Inhibitors: DNA Repair Pathway Complexity

Loss of Multiple DNA Repair Genes Can Sensitize to PARP Inhibition

Conclusions

PARP Inhibitors in the Treatment of Ovarian Cancer

The Homologous Recombination Pathway: Ideal Environment for PARP Inhibitors' Success

Study 19: PFS in All Patients and According to BRCA Status

NOVA: PFS in Patients With BRCA Mutations or Who Are HRD-Positive

SOLO2: Key Efficacy Outcomes

SOLO2: Key Efficacy Outcomes

ARIEL 3: Investigator-Assessed PFS

SOLO 2: AEs of Any Grade Reported in ≥10% of Patients in Either Arm

NOVA: TEAEs of Any Grade Reported in ≥10% of Patients in Either Arm

Single-Agent Therapy in BRCA-Mutated Ovarian Cancer: An Alternative?

Study 42: Olaparib Monotherapy in gBRCA-Mutated Ovarian Cancer

Study 10 and ARIEL 2: Rucaparib Monotherapy in gBRCA/sBRCA-Mutated Ovarian Cancer

Two Strategies for the Use of PARP Inhibitors in Advanced Ovarian Cancer

Where We Are Now: A Summary of Results With PARP Inhibitors

The Role of PARP Inhibitors in Breast Cancer Therapy

OLYMPIAD: PFS

OLYMPIAD: Summary of AEs, All Causality

OLYMPIAD: Additional Efficacy Data

OLYMPIAD: PFS in Relevant Subgroups

QoL in the OLYMPIAD Trial

Veliparib in a Randomized Phase 2 Study: BROCADE 2 - Grade 3/4 TEAEs

BROCADE 2: PFS

BROCADE 2: Tumor Response

Neoadjuvant Veliparib in Unselected TNBC: I-SPY2

ABRAZO Trial: Efficacy Results

ABRAZO: Hematologic Toxicities

Conclusions

Future Directions in Targeting DDR in Cancer: Conclusions

Discussion Overview

Multiple Malignancies Known to Associate With Homologous Recombination DDR

Clinical Response Rates by RECIST to Talazoparib 1 mg/day (Phase 2 Dose)

A Common Challenge for PARP Inhibitors: DNA Repair Pathway Complexity

Trial Design: A Chemical Screen in mCRPC Patients With Test and Validation Sets

Clinical Trial Results (TOPARP-A): Patient Characteristics

Primary Endpoint Analysis: Responses to Olaparib in Sporadic mCRPC

Germline Aberrations in DNA Repair in mCRPC

Antitumor Activity of Olaparib and Association With Defects in DNA Repair Genes

Multiple Combination Possibilities

Other DNA Repair Defects

Conclusions

Conclusions (cont)

Abbreviations

Abbreviations (cont)

Abbreviations (cont)

Abbreviations (cont)