Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 -- 1158 2023-06-21 03:50:47 |
2 references update Meta information modification 1158 2023-06-26 08:05:35 |

Video Upload Options

Do you have a full video?

Confirm

Are you sure to Delete?
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Paik, E.S.; Chang, H.K.; Lee, S. First-Line Maintenance PARP Inhibitor Treatment in Ovarian Cancer. Encyclopedia. Available online: https://encyclopedia.pub/entry/45897 (accessed on 18 June 2024).
Paik ES, Chang HK, Lee S. First-Line Maintenance PARP Inhibitor Treatment in Ovarian Cancer. Encyclopedia. Available at: https://encyclopedia.pub/entry/45897. Accessed June 18, 2024.
Paik, E Sun, Ha Kyun Chang, Sanghoon Lee. "First-Line Maintenance PARP Inhibitor Treatment in Ovarian Cancer" Encyclopedia, https://encyclopedia.pub/entry/45897 (accessed June 18, 2024).
Paik, E.S., Chang, H.K., & Lee, S. (2023, June 21). First-Line Maintenance PARP Inhibitor Treatment in Ovarian Cancer. In Encyclopedia. https://encyclopedia.pub/entry/45897
Paik, E Sun, et al. "First-Line Maintenance PARP Inhibitor Treatment in Ovarian Cancer." Encyclopedia. Web. 21 June, 2023.
First-Line Maintenance PARP Inhibitor Treatment in Ovarian Cancer
Edit

The therapeutic effect of Poly-ADP-ribose polymerase (PARP) inhibitor has been demonstrated in ovarian cancer patients with BRCA mutation or homologous recombination deficiency (HRD). HRD analysis at diagnosis determines treatment eligibility in ovarian cancer. In classifying the HRD patient group, different results may be observed depending on the test methods, and evidence of the possibility of differences in HRD prevalence between races was shown through representative clinical trial results.

PARP inhibitors ovarian cancer BRCA HRD prevalence

1. Introduction

Ovarian cancer has the poorest prognosis and the highest mortality among gynecological cancers [1]. Cytoreductive surgery and platinum-based chemotherapy are traditional standard treatment methods [2], and additional studies have reported that the use of the angiogenesis inhibitor bevacizumab increases progression-free survival (PFS) in high-risk groups [3]. Aggressive surgery, chemotherapy, and targeted therapy are applied to ovarian cancer treatment, but 70–75% of ovarian cancer patients still experience recurrence, and the 5-year survival rate is only 23%. There are still needs for additional treatment for ovarian cancer patients.
Poly-ADP-ribose polymerase (PARP) inhibitors are anti-cancer drugs, and the effectiveness of first-line maintenance therapy in the treatment of ovarian cancer patients has recently been proven through several studies [4][5][6][7]. Among ovarian cancer patients with BRCA mutation or homologous recombination deficiency (HRD), the efficacy of PARP inhibitors has been proven, and BRCA mutation and HRD are currently indicated for PARP inhibitor maintenance treatment. Approximately 11–15% of ovarian cancer patients have BRCA1/2 germline mutations, 7% have BRCA1/2 somatic mutations, and it has been reported that HRD is found in about 50% of patients with epithelial ovarian cancer [8][9].

2. HRD in Ovarian Cancer and PARP Inhibitor

Recently, HRD status has been proven as an important biomarker in ovarian cancer treatment with predictive and prognostic value. Approximately 50% of high-grade serous ovarian cancer is HRD according to the Cancer Genome Atlas (TCGA) project [10]. HRD is a complicated genomic signature that appears when cells cannot repair damaged double-stranded DNA via homologous recombination repair (HRR) pathway [11]. For maintaining genomic stability and cell function, cells must repair DNA damages. The compromised HRR pathway may lead to genomic instability in the form of genomic scarring, resulting in malignant transformation [12]. BRCA1 and BRCA2 as well as ATM, BARD1, BRIP1, H2AX, MRE11, PALB2, RAD51, RAD51C/D, RPA and Fanconi Anemia Complementation Group genes are representative genes that have important roles in the HRR pathway as important causative factors of HRD [13]. HRD-related genomic markers, known as “scars”, can be explained as abnormalities that cause structural modifications in chromosomes. The most substantial genomic scars are loss of heterozygosity (LOH) [14], telomeric–allelic imbalance (TAI) [15], and large-scale state transitions (LSTs) [16], which are components for assessment of the genomic instability score (GIS) to inform the status of HRD.
Actions of PARP inhibitors are based on synthetic lethality in HRD-positive tumor cells. PARP1 is an enzyme associated with the recovery of single-strand DNA breaks via the base excision pathway [17]. PARP inhibitor binds to PARP1 at single-strand DNA breaks to avoid effective repair and to cause DNA-protein crosslinks processing into double-strand breaks (DSB), which leads to increased genomic instability and cell death in BRCA1/2-mutated or other HRD-related cells that are defective in their DSB repair functions. Based on these findings, HRD has been identified as a prognostic biomarker for PARP inhibitor therapy in ovarian cancer, and other malignancies such as breast, pancreatic, and prostate cancer [18][19][20].

3. First-Line Maintenance PARP Inhibitor Treatment RCTs in Ovarian Cancer

The efficacy of PARP inhibitor as first-line maintenance therapy was shown in a number of clinical trials. In a phase 3 trial SOLO-1/GOG-3004/ENGOT [4], a total of 391 ovarian cancer patients with BRCA mutation (germline or somatic) were enrolled for efficacy of olaparib maintenance therapy. The median PFS for the olaparib group was 49.9 months, compared to 13.8 months in the placebo group with 70% reduced risk (hazard ratio [HR] 0.3; 95% confidence interval [CI] 0.23–0.41; p < 0.001). The SOLO-1 [4] was a representative study that marked the beginning of PARP inhibitor first-line maintenance in ovarian cancer patients, but it was conducted only for ovarian cancer patients with BRCA mutation. Information for HRD and BRCA wildtype ovarian cancer patients could not be provided. In the other trials using PARP inhibitor maintenance in ovarian cancer patients, the analysis was conducted for all patients and HRD was used as a criterion for stratification.
In a phase 3 trial of PRIMA/ENGOT-OV26/GOG-3012 [5], niraparib was investigated as a first-line maintenance therapy in patients with advanced-stage ovarian cancer patients regardless of BRCA status. A total of 733 ovarian cancer patients underwent randomization to receive niraparib or a placebo up to a 36-month period. In 373 patients with HRD, the median PFS was 21.9 months in the niraparib maintenance group compared to 10.4 months in the placebo group (HR 0.43; 95% CI 0.31–0.59; p < 0.001). In the overall population, the niraparib maintenance group had a median PFS of 13.8 months, compared to 8.2 months for the placebo group (HR 0.62; 95% CI 0.50–0.76; p < 0.001).
In the phase 3 VELIA/GOG-3005 [6] trial, veliparib as a maintenance treatment and alongside chemotherapy was evaluated. In this study, 1140 patients who had newly diagnosed advanced ovarian cancer were randomized in a 1:1:1 ratio. They were assigned to one of three treatment groups: chemotherapy plus placebo followed by placebo maintenance (control), chemotherapy plus veliparib followed by placebo maintenance (veliparib combination only), or chemotherapy plus veliparib followed by veliparib maintenance (veliparib throughout). The results showed that the median PFS in the veliparib throughout group was 23.5 months, which was significantly longer than the median PFS of 17.3 months in the placebo throughout group (HR 0.68; 95% CI 0.56–0.83; p < 0.001). In the BRCA-mutation cohort and HRD cohort, the veliparib throughout group showed a prominent reduced risk (HR 0.44; 95% CI 0.28–0.68; p < 0.001, and HR 0.57; 95% CI 0.43–0.76; p < 0.001, respectively).
In the PAOLA-1/ENGOT-OV25 trial [21], olaparib combined with bevacizumab as first-line maintenance in ovarian cancer patients was investigated. A study investigated 806 patients with newly diagnosed, advanced, high-grade ovarian cancer who had responded to platinum-taxane and bevacizumab. All participants received maintenance bevacizumab every 3 weeks for 15 months, and were randomized in a 2:1 ratio to receive either olaparib or placebo. The results showed that the median PFS for the olaparib/bevacizumab group was 22.1 months, which was significantly longer than the median PFS of 16.6 months in the placebo/bevacizumab group (HR 0.59; 95% CI 0.49–0.72; p < 0.001). In the subgroup of patients with HRD (n = 387), the PFS for the olaparib/bevacizumab group was even longer, with a median of 37.2 months, compared to 17.7 months in the placebo/bevacizumab group (HR 0.33; 95% CI 0.25–0.45). The absence of the olaparib-only maintenance group was limitation of this trial.
In an ATHENA (GOG-3020/ENGOT-ov45 trial [7], rucaparib as first-line maintenance in ovarian cancer patients was evaluated. A total of 538 patients with newly diagnosed, histologically confirmed, advanced (stage III–IV), high-grade epithelial ovarian cancer who had completed cytoreductive surgery (R0/complete resection was permitted) before chemotherapy or following neoadjuvant were enrolled for investigation. Patients were randomized 4:1 to receive rucaparib or a placebo as maintenance therapy. Median PFS was 28.7 months with rucaparib versus 11.3 months with placebo in the HRD population (HR 0.47; 95% CI, 0.31 to 0.72, p = 0.0004); 20.2 months versus 9.2 months in the intent-to-treat population (HR 0.52; 95% CI, 0.40 to 0.68; p < 0.0001) and 12.1 months versus 9.1 months in the HRD-negative population (HR 0.65; 95% CI 0.45 to 0.95).

References

  1. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249.
  2. Karam, A.; Ledermann, J.A.; Kim, J.W.; Sehouli, J.; Lu, K.; Gourley, C.; Katsumata, N.; Burger, R.A.; Nam, B.H.; Bacon, M.; et al. Fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup: First-line interventions. Ann. Oncol. 2017, 28, 711–717.
  3. Perren, T.J.; Swart, A.M.; Pfisterer, J.; Ledermann, J.A.; Pujade-Lauraine, E.; Kristensen, G.; Carey, M.S.; Beale, P.; Cervantes, A.; Kurzeder, C.; et al. A phase 3 trial of bevacizumab in ovarian cancer. N. Engl. J. Med. 2011, 365, 2484–2496.
  4. Moore, K.; Colombo, N.; Scambia, G.; Kim, B.G.; Oaknin, A.; Friedlander, M.; Lisyanskaya, A.; Floquet, A.; Leary, A.; Sonke, G.S.; et al. Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N. Engl. J. Med. 2018, 379, 2495–2505.
  5. González-Martín, A.; Pothuri, B.; Vergote, I.; DePont Christensen, R.; Graybill, W.; Mirza, M.R.; McCormick, C.; Lorusso, D.; Hoskins, P.; Freyer, G.; et al. Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N. Engl. J. Med. 2019, 381, 2391–2402.
  6. Coleman, R.L.; Fleming, G.F.; Brady, M.F.; Swisher, E.M.; Steffensen, K.D.; Friedlander, M.; Okamoto, A.; Moore, K.N.; Efrat Ben-Baruch, N.; Werner, T.L.; et al. Veliparib with First-Line Chemotherapy and as Maintenance Therapy in Ovarian Cancer. N. Engl. J. Med. 2019, 381, 2403–2415.
  7. Monk, B.J.; Parkinson, C.; Lim, M.C.; O’Malley, D.M.; Oaknin, A.; Wilson, M.K.; Coleman, R.L.; Lorusso, D.; Bessette, P.; Ghamande, S.; et al. A Randomized, Phase III Trial to Evaluate Rucaparib Monotherapy as Maintenance Treatment in Patients With Newly Diagnosed Ovarian Cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45). J. Clin. Oncol. 2022, 40, 3952–3964.
  8. Integrated genomic analyses of ovarian carcinoma. Nature 2011, 474, 609–615.
  9. Eoh, K.J.; Kim, H.M.; Lee, J.Y.; Kim, S.; Kim, S.W.; Kim, Y.T.; Nam, E.J. Mutation landscape of germline and somatic BRCA1/2 in patients with high-grade serous ovarian cancer. BMC Cancer 2020, 20, 204.
  10. Zhang, H.; Liu, T.; Zhang, Z.; Payne, S.H.; Zhang, B.; McDermott, J.E.; Zhou, J.Y.; Petyuk, V.A.; Chen, L.; Ray, D.; et al. Integrated Proteogenomic Characterization of Human High-Grade Serous Ovarian Cancer. Cell 2016, 166, 755–765.
  11. Yamamoto, H.; Hirasawa, A. Homologous Recombination Deficiencies and Hereditary Tumors. Int. J. Mol. Sci. 2021, 23, 348.
  12. O’Connor, M.J. Targeting the DNA Damage Response in Cancer. Mol. Cell. 2015, 60, 547–560.
  13. Ngoi, N.Y.L.; Tan, D.S.P. The role of homologous recombination deficiency testing in ovarian cancer and its clinical implications: Do we need it? ESMO Open 2021, 6, 100144.
  14. Abkevich, V.; Timms, K.M.; Hennessy, B.T.; Potter, J.; Carey, M.S.; Meyer, L.A.; Smith-McCune, K.; Broaddus, R.; Lu, K.H.; Chen, J.; et al. Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. Br. J. Cancer 2012, 107, 1776–1782.
  15. Birkbak, N.J.; Wang, Z.C.; Kim, J.Y.; Eklund, A.C.; Li, Q.; Tian, R.; Bowman-Colin, C.; Li, Y.; Greene-Colozzi, A.; Iglehart, J.D.; et al. Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents. Cancer Discov. 2012, 2, 366–375.
  16. Popova, T.; Manié, E.; Rieunier, G.; Caux-Moncoutier, V.; Tirapo, C.; Dubois, T.; Delattre, O.; Sigal-Zafrani, B.; Bollet, M.; Longy, M.; et al. Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation. Cancer Res. 2012, 72, 5454–5462.
  17. Helleday, T.; Petermann, E.; Lundin, C.; Hodgson, B.; Sharma, R.A. DNA repair pathways as targets for cancer therapy. Nat. Rev. Cancer 2008, 8, 193–204.
  18. Denkert, C.; Romey, M.; Swedlund, B.; Hattesohl, A.; Teply-Szymanski, J.; Kommoss, S.; Kaiser, K.; Staebler, A.; du Bois, A.; Grass, A.; et al. Homologous Recombination Deficiency as an Ovarian Cancer Biomarker in a Real-World Cohort: Validation of Decentralized Genomic Profiling. J. Mol. Diagn. 2022, 24, 1254–1263.
  19. Robson, M.E.; Tung, N.; Conte, P.; Im, S.A.; Senkus, E.; Xu, B.; Masuda, N.; Delaloge, S.; Li, W.; Armstrong, A.; et al. OlympiAD final overall survival and tolerability results: Olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Ann. Oncol. 2019, 30, 558–566.
  20. de Bono, J.; Mateo, J.; Fizazi, K.; Saad, F.; Shore, N.; Sandhu, S.; Chi, K.N.; Sartor, O.; Agarwal, N.; Olmos, D.; et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N. Engl. J. Med. 2020, 382, 2091–2102.
  21. Ray-Coquard, I.; Pautier, P.; Pignata, S.; Pérol, D.; González-Martín, A.; Berger, R.; Fujiwara, K.; Vergote, I.; Colombo, N.; Mäenpää, J.; et al. Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer. N. Engl. J. Med. 2019, 381, 2416–2428.
More
Information
Subjects: Oncology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : , ,
View Times: 194
Revisions: 2 times (View History)
Update Date: 26 Jun 2023
1000/1000
Video Production Service