Background
PARPs and DNA damage repair
Rationale for development of PARPi in breast cancer
Clinical application in breast cancer
Drug name | Pharmaceutical company | Current investigational phase in breast cancer |
---|---|---|
Olaparib (AZD2281) | AstraZeneca | Phase 3 studies in adjuvant and advanced settings in germline BRCAm breast cancer |
Veliparib (ABT-888) | Abbvie | Phase 3 study in neoadjuvant setting in combination with carboplatin and standard therapy in triple-negative breast cancer |
Phase 2/3 studies in advanced setting as combination therapy in germline BRCAm breast cancer | ||
Niraparib (formerly MK-4827) | Tesaro | Phase 3 study in advanced setting in germline BRCAm breast cancer |
Talazoparib (BMN-673) | BioMarin Pharmaceuticals | Phase 3 study in advanced setting in germline BRCAm breast cancer |
Phase 2 studies in advanced setting in BRCAm breast cancer | ||
Phase 2 study in advanced setting in germline BRCA intact breast cancer | ||
Phase 2 study in neoadjuvant setting in BRCAm breast cancer | ||
Rucaparib (formerly AG-14699) | Clovis Oncology | Phase 2 study in advanced setting in patients with known germline BRCAm solid tumors |
Phase 2 study in adjuvant setting in triple-negative breast cancer or germline BRCAm breast cancer | ||
CEP-9722 | Teva Pharmaceutical Industries | Phase 2 study in advanced setting in solid tumors |
Study Name (NCT) | Ref. | Phase | Tumor type | No. of patients | Investigation arm | Primary endpoint | Overall results | Results in BRCAm BC | Additional notes |
---|---|---|---|---|---|---|---|---|---|
[total/BC (BRCAm BC)] | |||||||||
Olaparib | |||||||||
NCT00516373 | [5] | 1 | Solid tumors | 60/9 (3) | Olaparib (10–600 mg bid) | PK, PD, safety and tolerability | ORR: 15 % | ORR 33 % | One CR in BRCAm BC lasting more than 60 weeks |
NCT00572364 | [119] | 1 | Solid tumors | 12/4 (NK) | Olaparib (100–400 mg bid) | Safety and tolerability | ORR: 8 % | – | One patient with BC and family history of BC had PR for 13 months |
NCT00494234 | [34] | 2 | BRCAm BC | 54/54 (54) | C1: olaparib (400 mg bid) | ORR | – | ORR C1: 41 % | |
C2: olaparib (100 mg bid) | ORR C2: 22 % | ||||||||
NCT00679783 | [7] | 2 | TNBC or BRCAm BC, HGSOC or BRCAm OC | 90/26 (10) | Olaparib (400 mg bid) | ORR | ORR in BC: 0 % | ORR: 0 % | Evidence of activity in non-BRCAm OC and platinum-resistant OC |
ORR in OC: 29 % | 50 % of unconfirmed PR (by RECIST) | ||||||||
NCT01078662 | [6] | 2 | BRCAm solid tumors | 317/62 (62) | Olaparib (400 mg bid) | ORR | ORR: 26 % | ORR: 13 % | Mean number of previous regimens for advanced disease: 4.6 |
DS ≥8 weeks: 47 % | |||||||||
Veliparib | |||||||||
NCT00892736 | [120] | 1 | TNBC, HGSOC and BRCAm BC and OC | 98/35 (14) | Veliparib (50–500 mg) | Tolerability | ORR in BRCAm: 24 % | ORR: 29 % | |
ORR in BRCA wt: 4 % | CBR: 57 % | ||||||||
Talazoparib | |||||||||
NCT01286987 | [32] | 1 | Solid tumors | 39/8 (6) | Talazoparib (25–1100 μg) | PK, PD, safety and anti-tumor activity | ORR: 65 % in BRCAm OC | ORR: 33 % | |
Niraparib | |||||||||
NCT00749502 | [31] | 1 | Solid tumors | 100/12 (4) | Niraparib (30–400 mg) | Safety and tolerability | ORR: 18 % in overall population, 40 % in BRCAm OC | ORR: 50 % | |
Rucaparib | |||||||||
NCT01482715 | 1–2 | BRCAm BC and OC | 56/27 (27) | Rucaparib (18 mg/m2) | ORR | Data mixed between OC and BC, at RP2D ORR: 80 % (4/5) | – |
Study name (NCT) | Ref. | Phase | Tumor type | No. of patients | Investigation arm | Primary endpoint | Overall results | Results in BRCAm BC | Additional notes |
---|---|---|---|---|---|---|---|---|---|
[total/BC (BRCAm BC)] | |||||||||
Olaparib | |||||||||
NCT00707707 | [122] | 1 | TNBC | 19/19 (NK) | Olaparib (200 mg bid) + PTX (90 mg/m2) | Safety and tolerability | ORR: 37 % | – | First- or second-line treatment only |
NCT00710268 | [79] | 1 | Solid tumors | 12/3 (NK) | Olaparib (100–400 mg bid) + BEV (10 mg/kg) | Safety and tolerability | No data on response reported | – | No grade 3 or 4 hematologic toxicities |
NCT00782574 | [23] | 1 | BC, OC, peritoneal cancer, pancreatic cancer | 54/42 (17) | Olaparib (50–200 mg bid continuously vs. intermittent) + CDDP (75 mg/m2) | Safety and tolerability | ORR: 41 % | ORR: 71 % | Continuous olaparib schedules not tolerable (hematologic toxicity) |
NCT01116648 | [45] | 1 | TNBC, OC | 28/8 (3) | Olaparib (100–400 mg bid) + cediranib (20–30 mg) | Safety and tolerability | Overall ORR: 29 % | ORR: 0 % | |
BC ORR: 0 % | |||||||||
BC CBR: 29 % | |||||||||
NCT01445418 | [123] | 1 | BRCAm OC and BC | 45/8 (8) | Olaparib (100–400 mg bid) + CBDCA (AUC 3–5) | Safety and tolerability | ORR: 52 % | ORR: 88 % | One CR in BRCAm BC for 3 months |
Veliparib | |||||||||
NCT00535119 | [124] | 1 | Solid tumors | 68/14 (NK) | Veliparib (20–120 mg) + CBDCA (AUC 5–6) + PTX (150–200 mg/m2) | PK, safety and tolerability | ORR: 19 % | – | One CR in BC |
NCT00740805 | [125] | 1 | Solid and hematologic tumors | 18/14 (5) | Veliparib (50–150 mg) + DOX (60 mg/m2) + CYC (600 mg/m2) | Tolerability | No overall results reported | ORR: 60 % | Expansion cohort study in BC ongoing |
NCT01063816 | [126] | 1 | Solid tumors | 59/10 (NK) | Veliparib (250 mg bid) + CBDCA (AUC 4) + GEM (800 mg/m2) | PK, safety and tolerability | ORR: 22 % | – | |
NCT01104259 | [53] | 1 | TNBC or BRCAm BC | 45/45 (12) | Veliparib (20–300 mg) + CDDP (75 mg/m2) + VNR (25 mg/m2) | Tolerability | ORR: 55 % | ORR: 73 % | |
NCT01251874 | [127] | 1 | BC | 44/44 (16) | Veliparib (50–200 mg) + CBDCA (AUC 5–6) | Safety and tolerability | ORR: 19 % | ORR: 25 % | |
NCT01445522 | [128] | 1 | Solid tumors and lymphomas | 35/12 (NK) | Veliparib (20–80 mg) + CYC (50 mg) | Safety and tolerability | ORR: 20 % | – | |
Not reported | [54] | 1 | BRCAm BC | 26/26 (26) | Veliparib (50–200 mg) + CBDCA (AUC 5–6) | Safety and tolerability | – | ORR: 46 % | |
CBF: 74 % | |||||||||
NCT01281150 | [55] | 1 | Solid tumors | 30/24 (5) | Veliparib (50–200 mg) + PTX (80 mg/m2) + CBDCA (AUC 5–6) | Tolerability | ORR: 48 % | ORR: 60 % | ORR in non-mutated BRCA BC: 67 % |
NCT01009788 | [52] | 2 | BC | 41/41 (8) | Veliparib (40 mg bid) + TMZ (150 mg/m2) | ORR | ORR: 13 % | ORR: 50 % | Expansion cohort with additional 20 patients with BRCA1/2 mutations: ORR 15 %, CBR: 45 % |
CBF: 63 % | |||||||||
Rucaparib | |||||||||
NCT01009190 | [129] | 1 | Solid tumors | 23/5 (NK) | Rucaparib (80–360 mg) + CBDCA (AUC 3–5) | Safety and tolerability | DCR: 50 % | – | |
CEP-9722 | |||||||||
NCT00920595 | [130] | 1 | Solid tumors | 26/7 (NK) | CEP-9722 (150–1000 mg) + TMZ (150 mg/m2) | PK, PD, safety and anti-tumor activity | ORR: 5 % | – |
Clinical trials in advanced disease
PARPi as single agent therapy
PARPi in combination therapy
Ongoing studies in the metastatic setting
Study name (NCT) | Ref. | Phase | Setting | Investigational arm(s) | Comparator arm(s) | Primary endpoint | Study status |
---|---|---|---|---|---|---|---|
Olaparib | |||||||
OlympiAD | [62] | 3 | ADV | Olaparib monotherapy | Physician’s choice CT | PFS | R |
(NCT02000622) | |||||||
OlympiA | [68] | 3 | ADJ | Olaparib monotherapy | Placebo | IDFS | R |
(NCT02032823) | |||||||
Veliparib | |||||||
BROCADE | [96] | 2 | ADV | Veliparib + | Placebo + | PFS | R |
(NCT01506609) | (Temozolomide) or | CBDCA + PTX | |||||
(CBDCA + PTX) | |||||||
(NCT02163694) | [63] | 3 | ADV | Veliparib + | Placebo + | PFS | R |
CBDCA + PTX | CBDCA + PTX | ||||||
Brightness | [74] | 3 | NADJ | (Veliparib + CBDCA) or (Placebo + CBDCA) + Neoadjuvant CT | Placebo + Neoadjuvant CT | pCR rate | R |
(NCT02032277) | |||||||
Talazoparib | |||||||
EMBRACA | [61] | 3 | ADV | Talazoparib monotherapy | Physician’s choice CT | PFS | R |
(NCT01945775) | |||||||
ABRAZO | [131] | 2 | ADV | Talazoparib monotherapy | Single arm study | ORR | R |
(NCT02034916) | |||||||
(NCT02282345) | [75] | 2 | NADJ | Talazoparib monotherapy | Single arm study | Safety | R |
Niraparib | |||||||
BRAVO | [60] | 3 | ADV | Niraparib monotherapy | Physician’s choice CT | PFS | R |
(NCT01905592) | |||||||
Rucaparib | |||||||
(NCT00664781) | [132] | 2 | ADV | Rucaparib monotherapy | Single arm study | ORR, safety | NR |
(NCT01074970) | [133] | 2 | ADJ | Rucaparib + | Cisplatin | 2y-DFS | NR |
Cisplatin |
Going beyond the metastatic setting
Safety of PARPi
Compound | Adverse event (range of occurrence across studies) | |
---|---|---|
Grade 1–2 | Grade 3–4 | |
Nausea (32–58 %) | ||
Fatigue (30–50 %) | ||
Vomiting (11–34 %) | Nausea (4–15 %) | |
Anorexia (12–27 %) | Fatigue (5–15 %) | |
Anemia (5–25 %) | Anemia (11–15 %) | |
Headache (22 %) | Vomiting (4–11 %) | |
Diarrhea (11–18 %) | Thrombocytopenia (3 %) | |
Taste alteration (13 %) | ||
Veliparib [135] | Dizziness (7 %) | – |
Nausea (7 %) | ||
Dysgeusia (7 %) | ||
Talazoparib [32] | Fatigue (26 %) | |
Nausea (26 %) | ||
Alopecia (grade 1 only, 26 %) | Neutropenia (8 %) | |
Anemia (13 %) | Thrombocytopenia (8 %) | |
Neutropenia (10 %) | Anemia (5 %) | |
Flatulence (10 %) | ||
Thrombocytopenia (3 %) | ||
Niraparib [31] | Anemia (48 %) | |
Nausea (42 %) | ||
Thrombocytopenia (35 %) | Thrombocytopenia (15 %) | |
Fatigue (34 %) | Anemia (10 %) | |
Anorexia (25 %) | Fatigue (8 %) | |
Neutropenia (24 %) | Neutropenia (4 %) | |
Constipation (23 %) | ||
Vomiting (19 %) | ||
Insomnia (10 %) | ||
Rucaparib [33]a | Fatigue (30–39 %) | |
Nausea (27–30 %) | ||
Diarrhea (13–20 %) | ||
Vomiting (23 %) | ||
Dizziness (17 %) | ||
Anorexia (11 %) |
Resistance to PARP inhibition
Mechanism of resistance | Proposed explanation | HR restoration |
---|---|---|
Restoration of BRCA functionality | Secondary mutation in BRCA1/2 | Potentially complete |
DNA damage repair rewiring | Mutations in p53 binding protein 1 | Partial |
Increased drug efflux | Overexpression of P-glycoprotein | None |
Increased activity of BRCA1/2 proteins | Increased stimulation of hypomorphic BRCA1/2 protein expression | Partial |
Decreased PARP expression | Epigenetic silencing or increased turnover | None |