PARP Inhibitors: The First Potential Treatment of Hereditary Ovarian Cancers


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Ursula A. Matulonis, MD

The European Medicines Agency approved olaparib maintenance therapy in both germline BRCA-mutant and germline BRCA–wild-type ovarian cancers following response to platinum-based chemotherapy.

—Ursula A. Matulonis, MD

Poly(ADP-ribose) polymerase (PARP) inhibitors are one of the most exciting new classes of agents in development for the treatment of ovarian cancer. Olaparib (Lynparza), the lead oral PARP inhibitor, received accelerated approval by the U.S. Food and Drug Administration (FDA) for the treatment of recurrent germline BRCA-mutant ovarian cancer in patients who have received at least three prior lines of chemotherapy.1,2

PARP inhibitors target a cancer cell’s inability to repair DNA, which occurs in cells that have BRCA mutations. Germline BRCA mutations have been identified in up to 17% of women with ovarian cancer and are associated with the high-grade serous histologic subtype, though other histologies can harbor BRCA mutations as well as mutations in other DNA repair genes.3,4

Currently, national guidelines have recommended that all patients with ovarian cancer regardless of histology undergo genetic testing for detection of high-risk inherited gene mutations.5

Background on PARP Inhibitors

Development of PARP inhibitors began in 2005, with the discovery that cancer cells with a BRCA mutation showed PARP inhibitor sensitivity through the concept of synthetic lethality, specifically in the treatment of cancers that harbor a BRCA mutation.6-8 Synthetic lethality occurs when a defect in a gene or protein still allows cell viability but will lead to death if combined with a defect in another gene or protein defect.

BRCA1 and BRCA2 genes encode proteins that are important in the repair of DNA double-strand breaks via homologous recombination. Cancer cells with defective BRCA1 or BRCA2 genes cannot perform homologous recombination properly, and thus the cells must use more error-prone DNA repair mechanisms, which then leads to an accumulation of genetic abnormalities.8 PARP inhibitors target these more errant DNA repair mechanisms, leading to cell death.

Emergence of Olaparib

Clinically, olaparib was first tested as a single agent in patients with heavily pretreated germline BRCA-mutant ovarian cancer, with observed response rates of up to 33% in both platinum-sensitive (platinum-free interval of 6 months or more) as well as platinum-resistant (platinum-free interval of less than 6 months) ovarian cancers.9,10

These studies also established the maximally tolerated dose of olaparib capsules—400 mg orally twice a day. Kaufman et al11 tested single-agent olaparib in cancer patients with germline BRCA mutations. A total of 193 patients with recurrent ovarian cancer were treated in this study, and 137 of these patients had received three or more prior lines of therapy. An accelerated FDA approval of olaparib capsules using the 400-mg dose twice daily was granted in December 2014, as monotherapy in patients with deleterious or suspected deleterious germline BRCA-mutant advanced ovarian cancer who had been treated with three or more prior lines of chemotherapy.

The indication was approved based on olaparib’s objective response rate of 34% and the median duration of response of 7.9 months in these patients.11 Combined results from olaparib monotherapy trials, including data from Kaufman et al, in the treatment of patients with ovarian cancer who received more than three lines of prior therapy provide additional supportive data for olaparib as monotherapy for recurrent germline BRCA-mutant ovarian cancer.12

Treatment Toxicities

Toxicities associated with olaparib included gastrointestinal problems, such as nausea, vomiting, abdominal pain, decreased appetite, diarrhea, and dyspepsia. Hematologic toxicities included anemia, neutropenia, thrombocytopenia, lymphopenia; increases in creatinine, arthralgia, and myalgia were also reported with olaparib.9-13

There have been rare cases of development of acute myeloid leukemia and myelodysplastic syndromes in heavily pretreated patients, so blood cell counts should be carefully monitored. If toxicities occur, the dose of olaparib can be reduced to either 200 mg twice daily or 100 mg twice daily.10

Olaparib Maintenance Therapy

A randomized, double-blind, placebo-controlled phase II study to evaluate maintenance therapy with olaparib in patients with or without a documented germline BRCA mutation, with platinum-sensitive, relapsed, high-grade serous ovarian cancer, found significant improvement in median progression-free survival with olaparib over placebo, 8.4 months vs 4.8 months, respectively (hazard ratio [HR] = 0.35, P < .001).14 To date, there has been no overall survival benefit reported with olaparib maintenance therapy.

In another phase II randomized study of olaparib maintenance therapy, women with germline BRCA mutations had an even more pronounced progression-free survival benefit—11.2 months vs 4.3 months (HR = 0.18, P < .0001)—in favor of olaparib maintenance compared with placebo.15

Based on these results, the European Medicines Agency approved olaparib as maintenance therapy in both germline BRCA-mutant and germline BRCA–wild-type ovarian cancer following response to a platinum-based chemotherapy in women with recurrent ovarian cancer.

In a post hoc analysis of these data recently presented at the 2015 Society of Gynecologic Oncology Annual Meeting,16 overall survival was significantly improved in favor of olaparib over placebo in patients with germline BRCA mutations in sites where patients on placebo who went on to receive a PARP inhibitor post disease progression were excluded.

The reason for their exclusion might have been that patients originally on placebo who eventually took a PARP inhibitor post disease progression may have had a confounding influence and effect on overall survival interpretation, thus reducing the perceived beneficial impact of olaparib in this population. However, this post-hoc analysis is limited by the small sample size and the need for additional maturity of the data.

Phase III Studies of Single-Agent Olaparib

Three international phase III studies of single-agent olaparib in germline BRCA-mutant ovarian cancer are ongoing. They include SOLO1, a randomized, double-blind, placebo-controlled trial of olaparib vs placebo in patients who have completed first-line platinum-based chemotherapy and have responded to upfront chemotherapy; SOLO2, a randomized, double-blind, placebo-controlled trial in patients with platinum-sensitive relapsed disease who have responded to platinum-based therapy; and SOLO3, a randomized, open-label trial of olaparib vs single-agent chemotherapy in patients with platinum-sensitive relapsed disease who have completed at least two lines of platinum-based therapy. SOLO1 and SOLO2 completed accrual at the end of 2014, and SOLO3 is currently accruing patients.

Additional PARP Inhibitors Under Study

In addition to olaparib, there are several other PARP inhibitors being tested in ovarian cancer, including the oral agents niraparib, rucaparib, veliparib, and BMN-673. Currently, niraparib, rucaparib, and veliparib are in phase III studies. Niraparib is being tested in a study called NOVA,17 which is similar in design to SOLO2 with the exception that patients with germline BRCA-mutant and germline BRCA–wild-type high-grade serous ovarian cancers are eligible to participate in the trial.

Rucaparib is being tested in the ARIEL3 study, which is investigating the drug’s effectiveness in women with high-grade serous platinum-sensitive relapsed ovarian cancer or endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer. And veliparib is being studied in patients with newly diagnosed advanced ovarian cancer.

Furthermore, PARP inhibitors are being investigated in combination with other agents, including antiangiogenics. The combination of olaparib and cediranib, an oral inhibitor of vascular endothelial growth factor receptor 2, was first tested in a phase I study of patients with recurrent epithelial ovarian or triple-negative breast cancer.18 The anticancer activity observed in that study led to a randomized phase II study of the drug combination vs single-agent olaparib in patients with platinum-sensitive recurrent ovarian cancer.19

The study results showed that the combination regimen resulted in prolonged progression-free survival, 17.7 months vs 9.0 months, over single-agent olaparib (HR = 0.42, P = .005). The overall response rate was higher for the combination therapy than for single-agent olaparib as well, 80% vs 48%, respectively (P = .002). In addition, the benefit of the combination therapy was especially pronounced in patients with germline BRCA–wild-type ovarian cancer, suggesting that the hypoxia induced by cediranib potentiates the homologous recombination defects of the cell and leads to augmented PARP inhibitor activity. There were more toxicities experienced by patients treated with the combination therapy compared with-single agent olaparib, and they included hypertension, fatigue, and gastrointestinal side effects.

The overall positive results of this phase II study have led to the development of two phase III studies: OVM1403 (for platinum-sensitive recurrent ovarian cancer) and OVM1405 (for platinum-resistant recurrent ovarian cancer).

Potential Impact on Overall Survival

The explosion of clinical trials investigating PARP inhibitors in the treatment of hereditary ovarian cancer has resulted in significantly improving progression-free survival. ■

Disclosure: Dr. Matulonis reported no potential conflicts of interest.

References

1. Liu JF, Konstantinopoulos PA, Matulonis UA: PARP inhibitors in ovarian cancer: Current status and future promise. Gynecol Oncol 133:362-369, 2014.

2. Olaparib (Lynparza) prescribing information, AstraZeneca Pharmaceuticals LP, December 2014. Available at www.lynparza.com. Accessed April 17, 2015.

3. Alsop K, Fereday S, Meldrum C, et al: BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: A report from the Australian Ovarian Cancer Study Group. J Clin Oncol 30:2654-2663, 2012.

4. Pennington KP, Walsh T, Harrell MI, et al: Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res 20:764-775, 2014.

5. National Comprehensive Cancer Network: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Available at http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed April 17, 2015.

6. Farmer H, McCabe N, Lord CJ, et al: Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917-921, 2005.

7. Bryant HE, Schultz N, Thomas HD, et al: Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434:913-917, 2005.

8. Lord CJ, Tutt AN, Ashworth A: Synthetic lethality and cancer therapy: Lessons learned from the development of PARP inhibitors. Annu Rev Med 66:455-470, 2015.

9. Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361:123-134, 2009.

10. Audeh MW, Carmichael J, Penson RT, et al: Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: A proof-of-concept trial. Lancet 376:245-251, 2010.

11. Kaufman B, Shapira-Frommer R, Schmutzler RK, et al: Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 33:244-250, 2015.

12. Matulonis UA, Penson RT, Domcheck SM, et al: Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: A multistudy subanalysis. 2015 Society of Gynecologic Oncology Meeting. Abstract 14.

13. Kaye SB, Lubinski J, Matulonis U, et al: Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly(ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer. J Clin Oncol 30:372-379, 2012.

14. Ledermann J, Harter P, Gourley C, et al: Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med 366:1382-1392, 2012.

15. Ledermann J, Harter P, Gourley C, et al: Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: A preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 15:852-861, 2014.

16. Matulonis UA, Harter P, Gourley C, et al: Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer and a BRCA mutation: Overall survival adjusted for post-progression PARP inhibitor therapy. 2015 Society of Gynecologic Oncology Meeting. Abstract 13.

17. Matulonis U, Mahner S, Wenham RM, et al: A phase 3 randomized double-blind trial of maintenance with niraparib versus placebo in patients with platinum-sensitive ovarian cancer (ENGOT-OV16/NOVA trial). 2014 ASCO Annual Meeting. Abstract TP5625.

18. Liu JF, Tolaney SM, Birrer M, et al: A phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer. Eur J Cancer 49:2972-2978, 2013.

19. Liu JF, Barry WT, Birrer M, et al: Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: A randomised phase 2 study. Lancet Oncol 15:1207-1214, 2014.

Dr. Matulonis is Director of Medical Gynecologic Oncology at Dana-Farber Cancer Institute and Associate Professor of Medicine at Harvard Medical School in Boston, Massachusetts.



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