BRCA Mutations in Ovarian and Prostate Cancer: Bench to Bedside
Abstract
:Simple Summary
Abstract
1. Introduction
2. Molecular Landscape
2.1. Homologous Recombination and Nonhomologous End Joining
2.2. Synthetic Lethality
2.3. Mismatch Repair (MMR)
3. Susceptibility to EOC
3.1. BRCA1 and BRCA2 Genes in EOC
3.2. Beyond BRCA1 and BRCA2 Genes in Ovarian Cancer
3.3. Tumour Testing in Ovarian Cancer
4. Susceptibility to Prostate Cancer
4.1. BRCA1 and BRCA2 Genes in Prostate Cancer
4.2. Beyond BRCA
4.3. Tumour Testing in Prostate Cancer
5. PARP Inhibitors Development across Tumour Types
5.1. Development of PARP Inhibitors in EOC
5.2. Development of PARP Inhibitors in Prostate Cancer
6. Developing Predictive Biomarkers for PARP Inhibitors
7. BRCA Mutations and Radiation Response
8. Conclusions and Future Directions
Author Contributions
Funding
Conflicts of Interest
References
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Study | Phase | Population | Treatment Arms | Outcome | P | Ref |
---|---|---|---|---|---|---|
STUDY 19 | II | (1) Platinum-sensitive, advanced HGSOC (2) At least two prior lines of platinum-based CTH (3) Unselected for BRCA status | (A) Olaparib 400 mg BID (B) Placebo | (A): Median PFS 1. Overall population: 8.4 vs. 4.8 m 2. BRCA mutants: 11.2 vs. 4.3 m 3. BRCA wild type: 7.4 vs. 5.5 m (B): OS 1. Overall population: 29.8 vs. 27.8 m 2. BRCA mutants: 34.9 vs. 31.9 m 3. BRCA wild type: 24.5 vs. 26.2 m (C): ORR 12% vs. 4% | (A1): <0.001 (A2): <0.0001 (A3): 0.0075 (B1): 0.44 (B2): 0.19 (B3): 0.96 (C): 0.12 | [112] |
STUDY 42 | II | (1) Platinum-resistant, advanced HGSOC (2) BRCA mutations | Olaparib 400 mg BID | (1) ORR: 34% (2) MDR: 7.9 m (3) PFS: 7 m (4) OS: 16.6 m | [113] | |
SOLO 2 | III | (1) Platinum-sensitive, advanced HGSOC or HGEOC (2) At least two prior lines of platinum-based CTH (3) BRCA mutations | (A) Olaparib 300 mg BID (B) Placebo | Median PFS: 19.1 vs. 5.5 m | <0.0001 | [114] |
ARIEL2 | II | Platinum-sensitive, advanced HGSOC or HGEOC | Rucaparib 600 mg BID | (A): Median PFS 1. BRCA mutants: 12.8 m 2. BRCA wild type LOH high: 5.7 m 3. BRCA wild type LOH low: 5.2 m (B): ORR 1. BRCA mutants: 80% 2. BRCA wild type LOH high: 39% 3. BRCA wild type LOH low: 13% | (A1): <0.0001 (A2): 0.011 (A3): 0.011 | [115] |
NOVA | III | (1) Platinum-sensitive, advanced HGSOC (2) At least two prior lines of platinum-based CTH (3) Stratification by gBRCAmut | (A) Niraparib 300 mg BID (B) Placebo | Median PFS (1) gBRCA mutants: 21 vs. 5.5 m (2) BRCA wild type HRD (+): 12.9 vs. 3.8 m (3) Overall non-gBRCA mutants: 9.3 vs. 3.9 m | (1): <0.0001 (2): <0.00001 (3): <0.0001 | [117] |
STUDY 10 | I/II | (1) Platinum-sensitive, advanced HGSOC or HGEOC; (2) gBRCAmut (phase II PART 2A) | Rucaparib 600 mg BID | (1) ORR: 59.5% (2) MDR: 7.8 m | [119] | |
SOLO 1 | III | (1) Platinum-sensitive, advanced HGSOC (2) BRCA mutations | (A) Olaparib 300 mg BID (B) Placebo | Median PFS: NR vs. 13.8 m 3-year PFS: 69% vs. 35% | <0.001 <0.001 | [120] |
SOLO 3 | III | Recurrent gBRCAm EOC | (A) Olaparib (B) CTH | Median PFS: 13.4 vs. 9.2 m | 0.013 | [121] |
PRIMA | III | Newly diagnosed advanced EOC with response to platinum-based CTH | (A) Niraparib 300 mg BID (B) Placebo | Median PFS (1) HRD (+): 21.9 vs. 10.4 m (2) Overall population: 13.8 vs. 8.2 m | (1): <0.001 (2): <0.001 | [122] |
QUADRA | II | (1) Platinum-sensitive, advanced HGSOC (2) HRD (+) | Niraparib 300 mg BID | (1) ORR 27.5% (2) DCR 68.6% | [123] | |
ARIEL3 | III | Recurrent EOC after response to platinum-based CTH | (A) Rucaparib 600 mg BID (B) Placebo | Median PFS (1) BRCA mutants: 16.6 vs. 5.4 m (2) HRD (+): 13.6 vs. 5.4 m (3) ITT population: 10.8 vs. 5.4 m | (1): <0.0001 (2): <0.0001 (3): <0.001 | [124] |
PAOLA-1 | III | Newly diagnosed, advanced, high-grade ovarian cancer with response after first-line platinum-taxane CTH plus bevacizumab | (A) Bevacizumab + olaparib maintenance (B) Bevacizumab + placebo | Median PFS (1) Overall population: 22.1 vs. 16.6 m (2) HRD (+): 37.2 vs. 17.7 m (3) HRD without BRCA mutations: 28.1 vs. 16.6 m | (1): <0.001 | [125] |
Clinical Trial ID | Phase | PARP Inhibitor | Population | PSA Response Rate | Primary Endpoint | Ref |
---|---|---|---|---|---|---|
NCT01682772 | II | Olaparib | mCRPC patients previously treated with abiraterone or enzalutamide, and cabazitaxel | 33% of patients (95%, 20–48) | RR, PSA, CTC | [130] |
NCT01682772 | II | Olaparib | mCRPC patients: (1) previously treated with one or two taxanes (2) DDR gene mutations | PSA levels decrease by ≥ 50%: 100% of BRCA2 and FANCA mutated mCRPC patients | RR, PSA, CTC | [131] |
NCT02987543 | III | Olaparib | mCRPC patients: (1) disease progression whilst on enzalutamide or abiraterone (2) ≥1 HRR gene mutation | Olaparib group: 30% of patients Control group: 10% of patients | rPFS | [132] |
NCT02952534 | II | Rucaparib | mCRPC patients: germline or somatic alteration in ≥1 prespecified HRR gene | 47.8% of BRCA-mutated patients (95%, 26.8–69.4) | ORR | [133] |
NCT04455750 | III | Rucaparib | mCRPC patients, resistant to testosterone-deprivation therapy | Not completed | rPFS, OS | [134] |
NCT02854436 | II | Niraparib | mCRPC patients: (1) DDR gene mutations (2) disease progression on taxane and AR-targeted therapy | 57% of patients (95% CI, 34–77) | ORR | [135] |
NCT03148795 | II | Talazoparib | mCRPC patients: (1) DDR-mutated (2) disease progression on taxane or AR-targeted therapy | Not completed | ORR | [136] |
NCT04821622 | III | Talazoparib | mCSPC patients with DDR gene mutations | Not completed | rPFS | [137] |
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Boussios, S.; Rassy, E.; Moschetta, M.; Ghose, A.; Adeleke, S.; Sanchez, E.; Sheriff, M.; Chargari, C.; Pavlidis, N. BRCA Mutations in Ovarian and Prostate Cancer: Bench to Bedside. Cancers 2022, 14, 3888. https://doi.org/10.3390/cancers14163888
Boussios S, Rassy E, Moschetta M, Ghose A, Adeleke S, Sanchez E, Sheriff M, Chargari C, Pavlidis N. BRCA Mutations in Ovarian and Prostate Cancer: Bench to Bedside. Cancers. 2022; 14(16):3888. https://doi.org/10.3390/cancers14163888
Chicago/Turabian StyleBoussios, Stergios, Elie Rassy, Michele Moschetta, Aruni Ghose, Sola Adeleke, Elisabet Sanchez, Matin Sheriff, Cyrus Chargari, and Nicholas Pavlidis. 2022. "BRCA Mutations in Ovarian and Prostate Cancer: Bench to Bedside" Cancers 14, no. 16: 3888. https://doi.org/10.3390/cancers14163888