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

Evolution and Revolution of 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 1 Pennington 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 inhibitors being tested in ovarian cancer PARP inhibitor Trials NCT# Olaparib SOLO1 (new dx) NCT01844986 SOLO2 NCT01874353 GY004 NCT02446600 GY005 NCT02502266 other combinations Veliparib GY3005 (new dx) NCT02470585 Rucaparib ARIEL 3 NCT01968213 Niraparib NOVA NCT01847274 Combination trials NCT02657889 with IO agent Talazoparib PARP after PARP NCT02326844 (BMN673) (NCI)

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 PI3K, HSP90 Cell: 144,2011, 646 - 674

Human ovarian cancer mouse xenograft models -- 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 AACR poster 1471 4/20/15 Sangeetha S. Palakurthi

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 BRCA m, 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 50 mg 300 mg 6 No DLTs expansion cohort) ASCO 2014 AACR 2015

Examples of combinations in ongoing clinical trials • PARP inhibitors and anti-angiogenic agents olaparib and cediranib • PARP inhibitors and PI3kinase pathway inhibitors olaparib and BKM120 (or BYL719) olaparib and AZD5363 • PARP inhibitors and immuno-oncology agents olaparib 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