Very sensitive cells to DNAdamaging agents Platinum compounds
- Slides: 52
Very sensitive cells to DNA-damaging agents (Platinum compounds and PARP inhibitors)
PREVALENCE OF BRCA MUTATIONS General population 0. 2– 0. 3% (2. 5% in Ashkenazi) Breast cancer 3% (25% in Ashkenazi) Breast cancer < 40 y 6% Familial history for breast cancer 20% Ovarian cancer 16% High-grade serous 30% Ann Transl Med 2017 Jul; 5(13): 275 Mol Diagn Ther 2015 Dec; 19(6): 351 -64
30% BRCA 1/2 mutated 20% germinal mutations 10% somatic mutations
Molecular subtypes of breast cancer
Approved treatment for ovarian cancer with BRCA 1/2 mutations OLAPARIB Operative staging/Surgery Diagnosis Progression chemotherepy 2 line maintenance Progression maintenance Death 3 line Recurrent ovarian cancer in response to platinum-based chemotherapy Olaparib Placebo PFS 19. 1 m 5. 8 m 0. 49 HR 0. 25 <0. 001 p <0. 0001 Olaparib Placebo PFS 8. 4 m 4. 8 m HR p Study 19 (NCT 00753545) SOLO-2 (NCT 01874353)
Approved treatment for breast cancer with BRCA 1/2 mutations Early BC Surgery Diagnosis Progression adjuvant Progression Surgery Diagnosis 1 line Progression 2 line other lines 3 line neoadjuvant Metastatic BC Progression Diagnosis 1 line Progression 2 line 3 line Death other lines NO SPECIFIC TREATMENT APPROVED Death
BUT………. . SOMETHING IS CHANGING
FDA-approved treatment for platinum-sensitive OC Operative staging/Surgery Diagnosis Progression chemotherepy maintenance 2 line Progression maintenance Olaparib (SOLO 2) Niraparib(NOVA) Rucaparib (ARIEL 3) NOVA (58%) Death 3 line --- g. BRCAm --- No prior BRCA test ARIEL-3 (35%)
Upfront trials in ovarian cancer with BRCAm Operative staging/Surgery Diagnosis Veliparib (GOG 3005) chemotherepy Progression 2 line maintenance Olaparib (SOLO 1) --- g. BRCAm Olaparib + Bev (PAOLA-1) Niraparib (PRIMA) --- g. BRCAm Progression maintenance Death 3 line
SOLO 1 in BRCAmut OC
PAOLA-1 in BRCAmut OC (300 mg/bid) For 2 years
PRIMA in platinum-sensitive OC
GOG 3005 trial in upfront therapy • Newly diagnosed high grade ovarian cancer • FIGO III-IV • Willing to undergo testing for g. BRCA • n=302 Carboplatin/Pacli + Veliparib Carboplatin/Pacli + Placebo six 21 -day cycles Veliparib Placebo up to 30 additional 21 -day cycles Primary endpoint • PFS Secondary endpoint • OS • DRS
First FDA-approved treatment for BRCAm breast cancer Surgery OLAPARIB Diagnosis Progression chemotherapy Progression Surgery Diagnosis 1 line Progression 2 line other lines 3 line chemotherapy OLAPARIB Progression Diagnosis 1 line Progression 2 line 3 line Death other lines Olympi. AD (NCT 02000622) study Death
Upfront trials in breast cancer with BRCAm Surgery Diagnosis Progression chemotherapy Progression Surgery Diagnosis chemotherapy 1 line Progression 2 line 3 line Olaparib (Olympi. AD) Talazoparib(EMBRACA) --- (< 3 lines) Talazoparib Carboplatin (TNT) Progression Diagnosis 1 line Carboplatin (TNT) Progression 2 line 3 line Olaparib (Olympi. AD) Talazoparib(EMBRACA) --- (< 3 lines) other lines Death
• Patients with g. BRCAm, HER 2 -negative MBC, who have received prior chemotherapy in the neoadjuvant, or metastatic setting • n=302 Olaparib 300 mg po, bid n= 205 Randomization (2: 1) Stratified by (i) prior use of chemotherapy for metastatic disease (ii) hormone receptor status, and (iii) previous use of platinum-based chemo. Physician’s choice of chemotherapy (capecitabine, vinorelbine, or eribulin) n=97 Primary endpoint • PFS (locally assessed per RECIST v 1. 1) Key secondary endpoint • OS
PFS Olaparib Chemo 7. 0 m 4. 2 m
OS Olaparib Chemo 19. 6 m 19. 3 m
Phase III EMBRACA Trial Abstract GS 6 -07 by Litton et al. n= 287 Primary endpoint • PFS (locally assessed per RECIST v 1. 1) n= 144 No more than 3 lines of chemotherapy Key secondary endpoint • OS • ORR
Patients characteristics Phase III EMBRACA Trial Prior chemotherapy for LA or MBC
Phase III EMBRACA Trial
Phase III EMBRACA Trial
Phase III EMBRACA Trial
Phase III EMBRACA Trial
Phase III EMBRACA Trial Hematologic toxicity Non-hematologic toxicity
Phase III EMBRACA Trial
Phase III EMBRACA Trial
Andrew Tutt et al. Nat Med. 2018 May; 24(5): 628 -637 Progression • Patients with newly diagnosed MBC TN or BRCAm (irrespective of ER, Pg. R and HER 2 status) or TN BRACAness • n=302 Carboplatin n= 188 Docetaxel N=188 Carboplatin R (1: 1) 6 -8 cycles q 21 days or until progression Primary endpoint • OR to cycle 6 • Secondary endpoint • PFS • OS
TNT Trial Overall population
TNT Trial
TNT Trial
Response to neoadjuvant talazoparib Median tumor volume decrease was 88% (range 30 -98%) after 2 months of talazoparib
Hematologic toxicity
Non-hematologic toxicity
Dose reduction
Future fornt-line therapy for ovarian cancer Stage IIIb-IV BRCA testing Wild-type Chemo + Bevacizumab GOG 218 ICON 7 Mutated Chemo +/- Bev Olaparib +/- Bev SOLO 1 PAOLA-1
Future fornt-line therapy for breast cancer Metastatic BRCA testing Wild-type Mutated Chemo Olaparib Talazoparib Olympi. AD EMBRACA
Future fornt-line therapy for breast cancer Neoaduvant BRCA testing Wild-type Mutated Chemo Talazoparib NCT 02282345
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