PARP inhibition as monotherapy or in combination with other novel - PowerPoint PPT Presentation

PARP inhibition as monotherapy or in combination with other novel agents: completed and ongoing studies Joyce Liu, MD, MPH Dana-Farber Cancer Institute, Boston MA

Verbal Disclosures • Consultant: AstraZeneca, Genentech/Roche

Agenda • PARP inhibitors as monotherapy in recurrent ovarian cancer • PARP inhibitors as maintenance therapy • Combination therapy with PARP inhibitors

PARP inhibitors in clinical development PARP Company Significant completed and ongoing trials in inhibitor ovarian cancer Olaparib AstraZeneca Single-agent monotherapy trials; Ph 2 maintenance study; SOLO1; SOLO2; SOLO3 Various combination studies Rucaparib Clovis Oncology ARIEL2; ARIEL3 Niraparib Tesaro NOVA; QUADRA; various combinations Veliparib AbbVie Single-agent Phase 2 (BRCA-mt); GOG-3005 Talazoparib Medivation PARP after PARP (NCT02326844) (formerly Biomarin)

PARP inhibitors as monotherapy in recurrent BRCA-mutated ovarian cancer • First report of clinical activity: Fong et al., 2009 – Phase 1 olaparib study • 50 patients with BRCA-mutated ovarian cancer enrolled – ORR: • Plat-sensitive: 62% • Plat-resistant: 42% – Degree of activity correlated with platinum-sensitivity Fong, N Engl J Med , 2009; Fong, J Clin Oncol, 2010

Clinical activity of PARP inhibitors in recurrent BRCA-mutated ovarian cancer Trial PARP Dosing Trial population Findings inhibitor characteristics Audeh et al. Olaparib 400mg BID Plat-sens or -res ORR : 33% (400mg); 13% (100mg) (capsule) 100mg BID Med prior lines 3 DOR : 290d; (400mg); 269d (100mg) Kaye et al. Olaparib 400mg BID <12mo PFI ORR : 31% (400mg); 25% (200mg); 18% (PLD) (capsule) 200mg BID PFS : 8.8mos (400mg); 6.5mos (200mg); 7.1 mos PLD 50mg/m2 (PLD) Kaufman et al. Olaparib 400mg BID Plat-res or unsuitable ORR : 31.1% (capsule) for further plat PFS : 7.0mos Mean prior lines 4.3 DOR : 225d Coleman et al. Veliparib 400mg BID ≤ 3 prior lines ORR : 26% PFS : 8.2mos Sandhu et al. Niraparib 30-400mg QD Plat-sens and -res ORR : 40% RP2D: 300mg QD DOR : 387d Kristeleit et al. Rucaparib 600mg BID Plat-sens ORR : 75% (ARIEL2) PFS : 12.8mos DOR : 9.5mos Audeh et al., Lancet 2010; Kaye et al., J Clin Oncol 2012; Kaufman et al., J Clin Oncol 2015; Coleman et al., Gyn Oncol 2015; Sandhu et al., Lancet Oncol 2015; Kristeleit et al., ECCO 2015

Clinical activity of PARP inhibitors in recurrent BRCA-mutated ovarian cancer Trial PARP Dosing Trial population Findings inhibitor characteristics Audeh et al. Olaparib 400mg BID Plat-sens or -res ORR : 33% (400mg) ; 13% (100mg) (capsule) 100mg BID Med prior lines 3 DOR : 290d; (400mg); 269d (100mg) Kaye et al. Olaparib 400mg BID <12mo PFI ORR : 31% (400mg); 25% (200mg); 18% (PLD) (capsule) 200mg BID PFS : 8.8mos (400mg); 6.5mos (200mg); 7.1 mos PLD 50mg/m2 (PLD) Kaufman et al. Olaparib 400mg BID Plat-res or unsuitable ORR : 31.1% (capsule) for further plat PFS : 7.0mos Mean prior lines 4.3 DOR : 225d Coleman et al. Veliparib 400mg BID ≤ 3 prior lines ORR : 26% PFS : 8.2mos Sandhu et al. Niraparib 30-400mg QD Plat-sens and -res ORR : 40% RP2D: 300mg QD DOR : 387d Kristeleit et al. Rucaparib 600mg BID Plat-sens ORR : 75% (ARIEL2) PFS : 12.8mos DOR : 9.5mos Audeh et al., Lancet 2010; Kaye et al., J Clin Oncol 2012; Kaufman et al., J Clin Oncol 2015; Coleman et al., Gyn Oncol 2015; Sandhu et al., Lancet Oncol 2015; Kristeleit et al., ECCO 2015

Clinical activity of PARP inhibitors in recurrent BRCA-mutated ovarian cancer Trial PARP Dosing Trial population Findings inhibitor characteristics Audeh et al. Olaparib 400mg BID Plat-sens or -res ORR : 33% (400mg); 13% (100mg) (capsule) 100mg BID Med prior lines 3 DOR : 290d; (400mg); 269d (100mg) Kaye et al. Olaparib 400mg BID <12mo PFI ORR : 31% (400mg); 25% (200mg); 18% (PLD) (capsule) 200mg BID PFS : 8.8mos (400mg); 6.5mos (200mg); 7.1 PLD 50mg/m2 mos (PLD) Kaufman et al. Olaparib 400mg BID Plat-res or unsuitable ORR : 31.1% (capsule) for further plat PFS : 7.0mos Mean prior lines 4.3 DOR : 225d Coleman et al. Veliparib 400mg BID ≤ 3 prior lines ORR : 26% PFS : 8.2mos Sandhu et al. Niraparib 30-400mg QD Plat-sens and -res ORR : 40% RP2D: 300mg QD DOR : 387d Kristeleit et al. Rucaparib 600mg BID Plat-sens ORR : 75% (ARIEL2) PFS : 12.8mos DOR : 9.5mos Audeh et al., Lancet 2010; Kaye et al., J Clin Oncol 2012; Kaufman et al., J Clin Oncol 2015; Coleman et al., Gyn Oncol 2015; Sandhu et al., Lancet Oncol 2015; Kristeleit et al., ECCO 2015

Olaparib compared to chemotherapy in BRCA -mutated ovarian cancer • Phase 2 randomized trial • 1:1:1 randomization • Olaparib 200mg BID Olaparib 400mg BID PLD 50mg/m2 • BRCA-mutated ovca • <12 mo platinum-free interval • No differences in response rates or PFS seen between olaparib and PLD arms Kaye et al., J Clin Oncol, 2011

Olaparib is active in BRCA-mutated ovarian cancer with ≥ 3 prior lines • 193 ovarian cancer pts – 137 pts with ≥ 3 prior lines • ORR: 31.1% • ORR ≥ 3 prior lines: 34% – Plat-sensitive: 46% – Plat-resistant: 30% – Plat-refractory: 14% • PFS ≥ 3 prior lines: 6.7 mos – Plat-sensitive: 9.4 mos – Plat-resistant: 5.5 mos Kaufman et al., J Clin Oncol 2015 Olaparib approved by FDA in December 2014 for this indication. Domchek et al., Gyn Oncol 2016

Ongoing trials of PARP inhibitors as monotherapy in BRCA-mutated ovarian cancer • SOLO3 – Olaparib compared to single-agent non-platinum based chemotherapy (weekly paclitaxel, topotecan, PLD, or gemcitabine) – Platinum-sensitive relapsed disease – At least two prior platinum-based lines of therapy • Talazoparib following PARPi – Eligibility includes progression on PARPi monotherapy within 2 months of screening visit – Patients should have responded to their prior PARPi

Case Study 1 A 64 year-old woman with high-grade serous ovarian cancer has previously been treated with three prior lines of chemotherapy. She now has disease progression on PLD. She is being treated in the US. Is she a candidate for olaparib therapy? A. Yes, if she has a family history of breast and ovarian cancer. B. Yes, if germline BRCA testing demonstrates a BRCA1 or BRCA2 mutation. C. No. D. Don’t know.

Case Study 1 She undergoes genetic testing and is found to have a deleterious BRCA1 mutation. She asks you what her likelihood is of responding to olaparib. What can you tell her about her likelihood of responding to olaparib? It is approximately: A. 75% B. 50% C. 30% D. 10%

Clinical activity of PARP inhibitors in non- BRCA-mutated ovarian cancers • ~50% of high grade serous ovarian cancers have alterations in HR repair genes (14% g BRCA ) • Two reported Ph 2 trials of PARPi monotherapy in BRCAwt ovca • Additional trials ongoing Konstantinopoulos et al., Cancer Discov, 2015

Olaparib demonstrates single-agent activity in BRCAwt ovarian cancer • Phase 2 trial – 17 gBRCAmt – 46 gBRCAwt • Olaparib 400mg BID (capsule) • ORR: – gBRCAmt: 41% – gBRCAwt: 24% • PFS: – gBRCAmt: 7.4 mos – gBRCAwt: 6.4 mos Gelmon et al., Lancet Oncol, 2011

Identifying a biomarker for HRD or PARPi responsiveness • Genome-wide alterations • Defects in HR lead to accumulation of genomic damage • Can include gains/losses of large chromosomal regions – LOH (loss of heterozygosity) – TAI (telomeric allelic imbalance) – LST (large scale state transitions) • Have been described as linked to presence of BRCA1/2 loss or HR deficiency

Rucaparib demonstrates activity in BRCAwt “biomarker-positive” ovarian cancer • ARIEL2 study (Part 1) – 206 patients – Plat-sensitive disease • Rucaparib 600mg BID • Tumor tissue classification – tBRCAmut – tBRCA-like (genomic LOH) – Biomarker negative Kristeleit et al., ECCO 2015

Rucaparib demonstrates activity in BRCAwt “biomarker-positive” ovarian cancer Kristeleit et al., ECCO 2015

Additional trials of PARP inhibitor monotherapy in BRCAwt ovarian cancer • ARIEL2 (Part 2) – Rucaparib 600mg BID – HGOC patients who have received ≥ 3 prior chemotherapy regimens – Using LOH biomarker described in ARIEL2 (Part 1) • QUADRA – Niraparib 300mg daily – HGSOC patients who have received ≥ 3 prior chemotherapy regimens – Will use Myriad HRD test as a biomarker for HRD

PARP inhibitors as maintenance therapy • Relatively low toxicity profile – Fatigue, nausea, vomiting – Marrow suppression • Phase 2 trial demonstrating PFS benefit compared to placebo • Multiple completed or ongoing Phase 3 trials in various clinical settings

Olaparib maintenance therapy improves PFS after platinum-based chemotherapy • Randomized double-blind trial • 265 patients – Platinum-sens disease recurrence – CR or PR to last plat-based therapy – Within 8 weeks of completing plat-based therapy • Olaparib 400mg BID or placebo Ledermann et al., NEJM 2012; Ledermann et al., Lancet Oncol 2014

PFS improvement with olaparib most pronounced in BRCAmt (germline/somatic) tumors Ledermann et al., Lancet Oncol 2014 Olaparib approved by EMA in December 2014 for maintenance therapy in platinum-sensitive BRCA-mutated ovarian cancer