Genetics: Beyond BRCA, Ursula Matulonis, MD
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1) PARP inhibitors work by preventing DNA repair in cancer cells with underlying DNA repair deficiencies like BRCA mutations, making them more susceptible to cell death. 2) Clinical trials show PARP inhibitors like olaparib and niraparib increase time to progression in platinum-sensitive ovarian cancer, including in patients without BRCA mutations. 3) Combining PARP inhibitors with other agents like angiogenesis inhibitors or immunotherapy may increase their effectiveness in additional patient subgroups.
Genetics: Beyond BRCA, Ursula Matulonis, MD
- 1. 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 Leader Gynecologic Oncology Program Dana-Farber Cancer Institute Associate Professor of Medicine Harvard Medical School Boston MA
- 2. Pertinent Conflicts of Interest: Consultant: Astrazeneca, Clovis Steering committee membership: Astrazeneca (Study 19), Tesaro (NOVA study)
- 3. 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
- 4. 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
- 5. 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 different types of ovarian cancer
- 6. 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 different types of ovarian cancer
- 7. 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 different types of ovarian cancer
- 8. 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 launched 2014: FDA gives accelerated approval to olaparib Timeline of PARP inhibitor development
- 9. Olaparib in germline BRCA+ Recurrent Ovarian Cancer: FDA approval based on ORR and DOR and not based on platinum sensitivity Response N = 137 Response 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.
- 10. PARP inhibitors in clinical trials for ovarian cancer PARP inhibitors Olaparib Veliparib Rucaparib Niraparib Talazoparib (BMN673)
- 11. PARP inhibitors in clinical trials for ovarian cancer PARP inhibitor Key Studies Ongoing or Completed Olaparib Phase III SOLO1: 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
- 12. 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 orally Disease progression by radiographic imaging NOVA study (niraparib): phase III study 1www.tesarobio.com Matulonis et al, ASCO 2014NCT01847274
- 13. 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 orally Disease 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.com Matulonis et al, ASCO 2014NCT01847274
- 14. 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)
- 15. 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
- 16. 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
- 17. 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
- 18. • 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
- 19. 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 1:1 Cediranib 30mg daily + Olaparib 200mg BID Olaparib 400mg BID Disease progression by radiographic imaging PI: Liu Liu et al, Lancet Oncology 2014 NCT01116648
- 20. 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, MPH Liu et al, Lancet Oncology 2014 NCT01116648
- 21. 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)
- 22. Novel PARP inhibitor combinations • HSP90 + PARP inhibitors: Heat shock protein 90 inhibitors: Preclinical data generated by Panos Konstantinopoulos using patient derived mouse xenograft models In development. • Immuno-oncology agents and PARP inhibitors: Phase I Pembrolizumab and Niraparib SU2C ovarian cancer grant NCT02657889, Phase I Olaparib and MEDI4736 (NCI) (NCT02484404)
- 23. 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
- 24. Next steps • PARP inhibitor roles in: New diagnoses of ovarian cancer Combinations 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? 24