Evolution and Revolution of PARP Targeting in Gynecologic - - PowerPoint PPT Presentation

Evolution and Revolution

• f PARP Targeting in

Gynecologic Malignancies

Ursula Matulonis, MD Dana-Farber Cancer Institute, Boston MA

Verbal Disclosures

• Advisory Boards for Genentech/Roche, Immunogen,

Merck

• Consulting for Astrazeneca (paid and unpaid)

Introduction and Overview

• Poly (ADP ribose) polymerase (PARP) inhibitors exploit homologous

recombination deficiency (HRD) in ovarian cancer; up to 50% of high grade serous cancers have HRD

• Other histologies display HRD (clear cell, endometrioid cancers) making

PARP inhibitors appropriate for many ovarian cancer patients

• Many PARP inhibitors are in ongoing ovarian cancer trials; some of

these are expected to report out in 2016

• Combinations of PARP inhibitors and other biologics may expand the

use of PARP inhibitors further

1Pennington CCR 2014

Many unanswered questions

• Who are appropriate patients to prescribe PARP

inhibitors for?

• What is next step after PARP inhibitor

progression?

• How to manage toxicities?
• Which patients are eligible for the new NRG

PARP inhibitor combination studies?

PARP enzymes have many mechanisms of action

Konstantinopoulos et al, CancerDisc 2015 Ceccaldi, D’Andrea et al, Nature 2015

PARP inhibitor Trials NCT# Olaparib SOLO1 (new dx) SOLO2 GY004 GY005

• ther combinations

NCT01844986 NCT01874353 NCT02446600 NCT02502266 Veliparib GY3005 (new dx) NCT02470585 Rucaparib ARIEL 3 NCT01968213 Niraparib NOVA Combination trials with IO agent NCT01847274 NCT02657889 Talazoparib (BMN673) PARP after PARP (NCI) NCT02326844

PARP inhibitors being tested in ovarian cancer

Today’s Agenda

• Shannon Westin: PARP inhibitor resistance and

strategies to restore PARP inhibitor sensitivity

• Joyce Liu: PARP inhibition as monotherapy or in

combination with other agents

• Ursula Matulonis: New directions for PARP

inhibitor use

New Directions in PARP inhibitor use

• Identification of cancers that will respond to

single agent PARP inhibitors

• PARP inhibitor combinations
• Understanding PARP inhibitor resistance
• Where/When to use single agents, combinations

Identification of cancers that will respond to single agent PARP inhibitors Different ways to measure HRD-ness

• BRCA testing – either germline or somatic
• Combination testing that includes LOH and other “scars”

to the cancer that indicate HRD

• HRD gene panel testing – i.e. BROCA

Combinations allow multiple pathways to be targeted

Cell: 144,2011, 646 - 674

PI3K, HSP90

Human ovarian cancer mouse xenograft models

AACR poster 1471 4/20/15 Sangeetha S. Palakurthi

• -Developed using ovarian cancer cells from patients’ ascites which are injected

intraperitoneally into NSG mice

• -Ovarian cancer cells are then lucerifized at P3 (secondary expansion of the

parental model)

• -Original lines developed by Joyce Liu (DFCI) and Ronny Drapkin (Penn)

Collaboration with Belfer Institute at Dana-Farber Cancer Institute

Combination Biologic Therapy

• Advantages:

1) Covers multiple aberrant pathways 2) Mitigate resistance strategies 3) Personalization of therapy 4) Non-chemotherapy regimens

• Disadvantages:

1) Phase I studies using a 3+3 design can take a long time 2) Overlapping toxicities 3) Which agents should be escalated 4) Showing that the “targets” are being hit 5) Possible drug drug interactions 6) Proof that the combination is effective compared to single agent 7) Selection of appropriate patients based on molecular eligibility such as BRCAm, HRDness, other mutations or profiles

Dose levels explored for olaparib and BKM120: trial started in 2012 and was first presented at ASCO 2014

Dose Level BKM120 (qd) Olaparib (BID) # of pts Status

• 1

40 mg 50 mg 6 No DLTs 0 (start dose) 60 mg 100 mg 3 **2 DLTs 1 40 mg 100 mg 6 No DLTs 2 40 mg 150 mg 3 No DLTs 3A 40 mg 200 mg 3 No DLTs 3B 50 mg 150 mg 3 No DLTs 4A 40 mg 300 mg 6 No DLTs 4B 50 mg 200 mg 6 No DLTs 5 60mg 300 mg 4 **2 AE’s 6 (chosen for expansion cohort) 50 mg 300 mg 6 No DLTs ASCO 2014 AACR 2015

Examples of combinations in ongoing clinical trials

• PARP inhibitors and anti-angiogenic agents
• laparib and cediranib
• PARP inhibitors and PI3kinase pathway

inhibitors

• laparib and BKM120 (or BYL719)
• laparib and AZD5363
• PARP inhibitors and immuno-oncology agents
• laparib and niraparib

New Directions in PARP inhibitor use

• Identification of cancers that will respond to

single agent PARP inhibitors

• PARP inhibitor combinations
• Understanding PARP inhibitor resistance
• Where/When to use single agents,

combinations: GY004 and GY005 should help