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
• varian cancer
• PARP inhibitors as maintenance therapy
• Combination therapy with PARP inhibitors

PARP inhibitors in clinical development

PARP inhibitor Company Significant completed and ongoing trials in

• varian 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 (formerly Biomarin) PARP after PARP (NCT02326844)

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
• varian 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

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

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

Clinical activity of PARP inhibitors in recurrent BRCA-mutated ovarian cancer

Trial PARP inhibitor Dosing Trial population characteristics Findings Audeh et al. Olaparib (capsule) 400mg BID 100mg BID Plat-sens or -res Med prior lines 3 ORR: 33% (400mg); 13% (100mg) DOR: 290d; (400mg); 269d (100mg) Kaye et al. Olaparib (capsule) 400mg BID 200mg BID PLD 50mg/m2 <12mo PFI ORR: 31% (400mg); 25% (200mg); 18% (PLD) PFS: 8.8mos (400mg); 6.5mos (200mg); 7.1 mos (PLD) Kaufman et al. Olaparib (capsule) 400mg BID Plat-res or unsuitable for further plat Mean prior lines 4.3 ORR: 31.1% PFS: 7.0mos DOR: 225d Coleman et al. Veliparib 400mg BID ≤3 prior lines ORR: 26% PFS: 8.2mos Sandhu et al. Niraparib 30-400mg QD RP2D: 300mg QD Plat-sens and -res ORR: 40% DOR: 387d Kristeleit et al. (ARIEL2) Rucaparib 600mg BID Plat-sens ORR: 75% 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 inhibitor Dosing Trial population characteristics Findings Audeh et al. Olaparib (capsule) 400mg BID 100mg BID Plat-sens or -res Med prior lines 3 ORR: 33% (400mg); 13% (100mg) DOR: 290d; (400mg); 269d (100mg) Kaye et al. Olaparib (capsule) 400mg BID 200mg BID PLD 50mg/m2 <12mo PFI ORR: 31% (400mg); 25% (200mg); 18% (PLD) PFS: 8.8mos (400mg); 6.5mos (200mg); 7.1 mos (PLD) Kaufman et al. Olaparib (capsule) 400mg BID Plat-res or unsuitable for further plat Mean prior lines 4.3 ORR: 31.1% PFS: 7.0mos DOR: 225d Coleman et al. Veliparib 400mg BID ≤3 prior lines ORR: 26% PFS: 8.2mos Sandhu et al. Niraparib 30-400mg QD RP2D: 300mg QD Plat-sens and -res ORR: 40% DOR: 387d Kristeleit et al. (ARIEL2) Rucaparib 600mg BID Plat-sens ORR: 75% 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

• laparib 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 Domchek et al., Gyn Oncol 2016

Olaparib approved by FDA in December 2014 for this indication.

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

• laparib. What can you tell her about her likelihood of responding to
• laparib? 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% gBRCA)

• Two reported Ph 2 trials
• f 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

Completed and ongoing trials of PARP inhibitor maintenance therapy

Trial PARP inhibitor Dosing Trial population characteristics Status Upfront SOLO1 (NCT01844986) Olaparib (tablet) 300mg BID BRCAmt ovarian cancer Following upfront surgery and chemotherapy Accrual completed PAOLA1 (NCT02477644) Olaparib (tablet) 300mg BID Following upfront surgery and chemotherapy (also with bevacizumab) Accrual ongoing Recurrent SOLO2 (NCT01874353) Olaparib (tablet) 300mg BID BRCAmt ovarian cancer Platinum-sensitive recurrence Following response to plat-based chemotherapy Accrual completed NOVA (NCT01847274) Niraparib 300mg daily gBRCAmt or HGSOC Platinum-sensitive recurrence Following response to plat-based chemotherapy Accrual completed ARIEL3 (NCT01968213) Rucaparib 600mg BID HGOC Platinum-sensitive recurrence Following response to plat-based chemotherapy Accrual ongoing

Case Study 2

You have been treating a 49 year-old woman with a germline BRCA2 mutation for recurrent platinum-sensitive ovarian cancer. She has had 6 cycles of carboplatin and PLD with a complete clinical response. Which of the following is not true about maintenance therapy with PARP inhibitors in this setting? A. Olaparib is approved by the FDA for maintenance therapy in this setting. B. Olaparib is approved by the EMA for maintenance therapy in this setting. C. Olaparib maintenance therapy significantly prolongs PFS compared to placebo in this setting.

Combination therapy with PARP inhibitors

• Combining PARP inhibitors

with chemotherapy challenging due to hematologic toxicity

• Combination therapy with
• ther targeted therapies

attractive due to non-

• verlapping toxicities

– Potential to overcome PARPi resistance – Sensitize previously PARPi insensitive populations by inducing HR-deficient states

Trial Treatments Status/Results Recurrent Oza et al.

(Lancet Oncol 2015)

• 1. Carbo AUC6/paclitaxel 175mg/m2
• 2. Carbo AUC4/paclitaxel

175mg/m2/olap 200mg BID d1-10 q21d+olap maintenance Improved PFS (12.2 vs 9.6 mos) with

• laparib

Upfront GOG3005

• 1. Carbo/paclitaxel
• 2. Carbo/paclitaxel/veliparib
• 3. Carbo/paclitaxel/veliparib

+veliparib maintenance *veliparib dosed 150mg BID Accrual ongoing

Combining PARP inhibition and anti- angiogenics

• PARPi or PARP KO causes

decreased in vivo angiogenesis

• DNA damage response are

altered in setting of hypoxia

– RAD51, BRCA1, BRCA2, and

• ther proteins of HR are

downregulated in hypoxic conditions1-3

• Sensitivity to PARP inhibitor can

be increased in hypoxic conditions2

1Bindra et al., Oncogene 2007 2Chan et al., Cancer Res 2010 3Lim et al., Neoplasia 2014

Control Hypoxia + RAD51 Hypoxia

1Bindra et al., Oncogene 2007 2Chan et al., Cancer Res 2010

Combination cediranib and olaparib

• Phase 2 open-label study
• Randomized 1:1 to cediranib/olaparib or olaparib
• Platinum-sensitive ovarian cancer
• Stratified by prior receipt of bevacizumab (upfront only allowed) and

BRCA mutation status (gBRCAmt vs. gBRCAwt/unknown)

Cediranib 30mg daily + Olaparib capsules 200mg BID Olaparib capsules 400mg BID Disease progression by RECIST v1.1 criteria Dx platinum- sensitive recurrent

• varian cancer

Randomize 1:1

Combination cediranib and olaparib improves PFS compared to olaparib alone

Olaparib Ced/Olap PFS events 28 19 Median PFS 9.0 mo 17.7 mo p=0.005 HR 0.42 (95% CI: 0.23-0.76) Liu et al., Lancet Oncol 2014

Cediranib/olaparib significantly increased PFS in patients without a BRCA mutation

BRCA Mutation Carrier BRCA Non-carrier/Unknown Olaparib Ced/Olap Olaparib Ced/Olap PFS events 13 10 15 9 Median PFS 16.5 mo 19.4 mo 5.7 mo 16.5 mo p=0.16 p=0.008 HR 0.55 (95% CI: 0.24-1.27) HR 0.32 (95% CI: 0.14-0.74)

Cediranib/olaparib in current development: NRG-GY004

Target accrual: 450 pts Stratify:

• Germline BRCA status (testing

required on all pts)

• Prior anti-angiogenic
• Plat-free interval

Primary study endpoint:

• Efficacy (PFS)

Key secondary study endpoints:

• Patient-reported outcomes

(NFOSI-DRS-P)

• Additional efficacy endpoints

Study Chair: Joyce Liu; Co-Chair: Ursula Matulonis

Study Chair: Jung-Min Lee; Co-Chair: Angeles Secord

Cediranib/olaparib in current development: NRG-GY005 (COCOS)

Primary study endpoint:

• Efficacy
• Phase 2: PFS
• Phase 3: PFS/OS

Key secondary study endpoints:

• Patient-reported outcomes

(NFOSI-DRS-P)

• Additional efficacy endpoints

Additional anti-angiogenic/PARP inhibitor combination trials in development

• Niraparib + bevacizumab (AVANOVA; NCT02354131)

– Phase 1 (AVANOVA1): Niraparib + bevacizumab – Phase 2 (AVANOVA2): Niraparib vs. bevacizumab (with crossover to niraparib after progression) vs. niraparib/bevacizumab in plat- sens ovarian cancer

• Cediranib + olaparib after progression on olaparib

(NCT02340611)

– Addition of cediranib for patients who have responded to olaparib for at least 6 months

• Cediranib + olaparib biomarker trial in recurrent ovarian

cancer (plat-sens or -res; NCT02345265)

PARP inhibitors combined with PI3K pathway inhibitors

• PI3K inhibition can lead to DNA

damage and downregulation of BRCA1/2 in TNBC

• Synergy between BKM120 and
• laparib in BRCA-def breast

cancer mouse model

• Phase 1 trials demonstrate

activity of PI3K pathway inhibitor + PARPi combination

– Olaparib + BKM120 – Olaparib + AZD5363 (AKTi) – Olaparib + BYL719 (ongoing)

Matulonis et al., AACR 2015

Additional PARPi combinations of interest

Combination Rationale Status Olaparib + durvalumab (PD-L1)

• BRCAmt HGSOCs with higher neoantigen load,

increased TILs, and increased PD-1/PD-L1 expression1

• PARPi may have immunoregulatory effects2

Ph 1; accrual ongoing (NCT02484404) Niraparib + pembrolizumab (PD-1) (KEYNOTE-162) As above Ph 1/2; accrual ongoing (NCT02657889) Veliparib + dinaciclib (CDK1)

• CDK1 inhibition induces HR deficiency3
• CDK1 inhibition sensitizes HR proficient cells to PARP

inhibitors in vitro3 Ph 1; accrual ongoing (NCT01434316) Olaparib + AZD1775 (Wee1)

• Wee1 inhibition with activity in BRCA-mutated

cancers4

• PARP inhibition could increase genomic instability,

leading to greater dependence on cell cycle Ph 1; accrual ongoing (NCT02511795) PARP inhibitor + HSP90 inhibitor

• BRCA1 and other HR pathway genes are HSP90 client

proteins5 Pre-clinical PARP inhibitor + HDAC inhibitor

• HDAC inhibition can result in downregulation of HR

pathway genes6 Pre-clinical

1Strickland et al., Oncotarget 2016; 2Huang et al., Biochem Biophys Res Commun 2015; 3Johnson et al., Nat Med 2011; 4Do et al., J Clin Oncol 2015; 5Choi et al., Oncotarget 2014; 6Konstantinopoulos et al., Gyn Oncol 2014

Summary

• PARP inhibitor monotherapy is active in BRCA-mutated ovarian

cancer

• A subset of BRCA-wild type ovarian cancer also responds to PARP

inhibitor monotherapy

– Challenges remain in identifying an effective biomarker

• PARP inhibitors as maintenance therapy can extend PFS in

platinum-sensitive recurrence

– Multiple Phase 3 trials will further define in which patients a maintenance approach might be appropriate

• PARP inhibitor combinations have powerful potential

– Overcoming PARP inhibitor resistance – Broadening the population who will respond to PARP inhibitors