Targeting BRCA for Therapeutic Benefit:

Update on PARP inhibitors as a treatment for all subtypes of ovarian cancer

Ursula Matulonis, M.D.Director and Program LeaderGynecologic Oncology ProgramDana-Farber Cancer InstituteAssociate Professor of Medicine Harvard Medical School Boston MA

Pertinent Conflicts of Interest:Consultant: Astrazeneca, ClovisSteering committee membership: Astrazeneca (Study 19), Tesaro (NOVA study)

What are PARP inhibitors?

• PARP = poly (ADP ribose) polymerase• PARP is an enzyme that helps repair damaged DNA.

Damage to DNA is caused by many events (UV light, radiation, etc).

• Inhibiting the PARP enzyme with a PARP inhibitor prevents the DNA from repairing itself; cell then dies.

• Cancer cells with underlying vulnerabilities in repairing DNA such as those with an abnormal BRCA gene are more susceptible to PARP inhibitors

Spectrum of the degree of cancer cell susceptibility to PARP inhibitors; (i.e. definitions of “BRCAness”)

• BRCA positive: Presence of a BRCA mutation (either germline or tumor)

• HRD positive:HRD = Homologous recombination deficiency (Underlying defects in DNA repair are present in the cancer) positive as defined by testing the tumor’s DNA

• HRD negative: No BRCA mutation and the HRD test is negative

High grade serous cancers: Homologous recombination deficiency (HRD) is common and thus displays high rate of platinum and PARP inhibitor sensitivity

Serous

Endometrioid

Mucinous

Clear cell

Low grade High grade

PARP inhibitors exploit HRD presence in differenttypes of ovarian cancer

High grade serous cancers: Homologous recombination deficiency (HRD) is common and thus displays high rate of platinum and PARP inhibitor sensitivity

Serous

Endometrioid

Mucinous

Clear cell

Low grade High grade

PARP inhibitors exploit HRD presence in differenttypes of ovarian cancer

High grade serous cancers: Homologous recombination deficiency (HRD) is common and thus displays high rate of platinum and PARP inhibitor sensitivity

Serous

Endometrioid

Mucinous

Clear cell

Low grade High grade

Important!Other histologies of ovarian cancer also have DNA repair defects making them susceptible to PARP inhibitors or PARP inhibitor combinations

PARP inhibitors exploit HRD presence in differenttypes of ovarian cancer

2005: first evidence in the lab that PARP inhibitors work in BRCA+ cancer cells 2007-08: First patients showing benefit from PARP inhibitors and phase II trials of olaparib launched 2009: Combination trials are launched 2012: Olaparib shows benefit as maintenance therapy following platinum based chemotherapy (study 19)2013: Other Phase III PARP inhibitor trials are launched2014: FDA gives accelerated approval to olaparib

Timeline of PARP inhibitor development

Olaparib in germline BRCA+ Recurrent Ovarian Cancer: FDA approval based on

ORR and DOR and not based on platinum sensitivity

Response N = 137Response rate 34%Median Duration of response 7.9 months

Olaparib FDA approval on 12/20/14:Olaparib as monotherapy in pts with deleterious/suspected deleterious gBRCA recurrent ovarian cancer treated with ≥3 lines of chemotherapy.

Study 42: Kaufman B, et al. J Clin Oncol. 2015;33:244-250.

PARP inhibitors in clinical trials for ovarian cancer

PARP inhibitors

Olaparib

Veliparib

Rucaparib

Niraparib

Talazoparib (BMN673)

PARP inhibitors in clinical trials for ovarian cancer

PARP inhibitor

Key Studies Ongoing or Completed

Olaparib Phase IIISOLO1: new diagnosis, maintenance, BRCA+ (NCT01844986)SOLO2: maintenance post-platinum, BRCA+ (NCT01874353)

GY004: olap/cediranib vs platinum for sensitive relapse (NCT02446600)GY005: olap/cediranib vs single agents for resistant relapse(NCT02502266)

Veliparib Phase III: newly diagnosed ovarian cancer: still accruing (NCT02470585)

Rucaparib Phase III: ARIEL3 (still accruing) (NCT01968213)Phase II: ARIEL2 given FDA breakthrough status in 2015 (NCT01891344)

Niraparib Phase III: NOVA (NCT01847274)Reported positive results on June 28, 2016

Presented by: Joyce Liu, MD, MPH

• Randomized multi-center Phase 3 study, international study, double blinded study

• Stratified for BRCA mutation and HRD test done retrospectively • Eligibility criteria included:

– Platinum-sensitive relapsed high grade ovarian cancer

Dx platinum-sensitive recurrent

ovarian cancer, received

platinum and there is an anti-

cancer response

Randomize 2:1(niraparib

vs.placebo)

Placebo

Niraparib 300 mg every day

orallyDisease

progression by radiographic

imaging

NOVA study (niraparib): phase III study

1www.tesarobio.comMatulonis et al, ASCO 2014NCT01847274

Presented by: Joyce Liu, MD, MPH

• Randomized multi-center Phase 3 study, international study, double blinded study

• Stratified for BRCA mutation and HRD test done retrospectively • Eligibility criteria included:

– Platinum-sensitive relapsed high grade ovarian cancer

Dx platinum-sensitive recurrent

ovarian cancer, received

platinum and there is an anti-

cancer response

Randomize 2:1(niraparib

vs.placebo)

Placebo

Niraparib 300 mg every day

orallyDisease

progression by radiographic

imaging

NOVA study (niraparib): phase III study

NOVA Results released in a press release on June 28, 20161:

Increased time in remission for women receiving niraparib compared to placebo who have a

BRCAm as well as for the group of women whose cancers were HRD positive. Some benefit too from niraparib versus placebo for the women

whose cancers were HRD negative

1www.tesarobio.comMatulonis et al, ASCO 2014NCT01847274

Can PARP inhibitors be used in ovarian cancer without abnormalities of BRCA?

• Single agent PARP inhibitors in BRCA negative cancers (niraparib, rucaparib)

• Combinations of PARP inhibitors and other biologic agents (GY004 and GY005)

Figure 6 Therapeutic Targeting of the Hallmarks of Cancer Drugs that interfere with each of the acquired capabilities necessary for tumor growth and progression have been developed and are in clinical trials or in some cases approved for clinical use.

Cell, Volume 144, Issue 5, 2011, 646 - 674

Cancer is complex

Figure 6 Therapeutic Targeting of the Hallmarks of Cancer Drugs that interfere with each of the acquired capabilities necessary for tumor growth and progression have been developed and are in clinical trials or in some cases approved for clinical use.

Cell, Volume 144, Issue 5, 2011, 646 - 674

Cancer is complex

Phase 1 study of cediranib (Oral VEGFR1, 2, and 3 inhibitor) and olaparib demonstrated

activity in ovarian cancer patients: NCT01116648

Presented by: Joyce Liu, MD, MPH

• Dose escalation study of cediranib and olaparib in recurrent ovarian and triple negative breast cancer

• This study:--Showed significant anti-cancer activity of the combination--Established the dosing for both drugs so that the randomized phase II could begin

Presented by: Joyce Liu, MD, MPH

Liu et al., Eur J Cancer 2013

Phase 1 study of cediranib (Oral VEGFR1, 2, and 3 inhibitor) and olaparib demonstrated

activity in ovarian cancer patients: NCT01116648

Presented by: Joyce Liu, MD, MPH

Phase 2 Study Design• Randomized multi-center open-label Phase 2 study• Eligibility criteria included:

– Platinum-sensitive relapsed ovarian cancer– High-grade serous or endometrioid histological subtype– Other high-grade histological subtypes with known germline BRCA mutation allowe

Dx platinum-sensitive recurrent ovarian cancer

Randomize 1:1Cediranib

30mg daily + Olaparib

200mg BID

Olaparib 400mg BID

Disease progression by radiographic

imaging

PI: Liu

Liu et al, Lancet Oncology 2014 NCT01116648

Primary Outcome: Cediranib/olaparib significantly increased the time the cancer stayed in remission for compared to olaparib alone

Benefit for the combination was much more pronounced for BRCA negative cancers than BRCA positive cancers

Why? Perhaps the anti-angiogenic effect of cediranib makes the cancer cell more susceptible to the effects of a PARP inhibitor

Presented by: Joyce Liu, MD, MPHLiu et al, Lancet Oncology 2014 NCT01116648

Phase III NCI-sponsored olaparib and cediranib studies in recurrent ovarian cancer

• NRG-GY004 (platinum sensitive)olaparib vs olaparib/cediranib vs platinum doublet (PI’s: Liu/UAM) (NCT02446600)

• NRG-GY005 (platinum resistant)olaparib (or cediranib) vs olaparib/cediranib vs single agent chemotherapy(PI’s: Lee/Secord) (NCT02502266)

Novel PARP inhibitor combinations

• HSP90 + PARP inhibitors:Heat shock protein 90 inhibitors: Preclinical data generated by Panos Konstantinopoulos using patient derived mouse xenograft modelsIn development.

• Immuno-oncology agents and PARP inhibitors:Phase I Pembrolizumab and NiraparibSU2C ovarian cancer grantNCT02657889,

Phase I Olaparib and MEDI4736 (NCI) (NCT02484404)

Other combinations• PARP and PI3K inhibitors

(NCT01623349)• Wee1 and PARP inhibitors (Astrazeneca, Dana-Farber, and

MDAnderson)• Anti-BCL2 and MEK inhibitors

(Joan Brugge lab HMS)

Combination development needs to be driven by rationale, expected side effects, and cancer pre-selection

Next steps

• PARP inhibitor roles in:New diagnoses of ovarian cancerCombinations with other agents that interfere with DNA repair, immunotherapy agents, etc.

• Why are certain cells more sensitive or resistant to PARP inhibitors?

• How does a cancer cell eventually become resistant to a PARP inhibitor and what is the treatment strategy then?

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