Novel Agents Signal Progress in the Management of Platinum-Resistant Ovarian Cancer

OncologyLive, October 2015, Volume 16, Issue 10

Partner | Cancer Centers | <b>LSU Stanley S. Scott Cancer Center</b>

The evaluation of noncytotoxic agents for the treatment of epithelial ovarian cancer has produced encouraging findings in recent months, which has led to the approval of new agents with novel mechanisms of action and continuing studies into many more potential therapies.

Agustin A. Garcia, MD

Professor of Medicine and Section Chief

Hematology Oncology

Louisiana State University

New Orleans, LA

The evaluation of noncytotoxic agents for the treatment of epithelial ovarian cancer has produced encouraging findings in recent months. This has led to the approval of new agents with novel mechanisms of action and continuing studies into many more potential therapies.

These are welcome developments for the treatment of patients with this malignancy. This includes approximately 22,000 women who are diagnosed annually with ovarian cancer in the United States alone.1

Although epithelial ovarian cancer is a highly chemoresponsive tumor initially, the development of resistance is a common event. In fact, the majority of women with stage III-IV ovarian cancer, the most common stage at presentation, will relapse and eventually succumb to their disease.

The Cytotoxic Therapy Landscape

This review will focus on recent clinically relevant findings of noncytotoxic agents for the treatment of ovarian cancer, including an expanded indication for bevacizumab (Avastin) and a new drug approval for olaparib (Lynparza).The initial management of ovarian cancer typically includes a staging and debulking surgical intervention and a platinum plus taxane—based chemotherapy regimen. At the completion of this therapy, most patients will have no evidence of disease. However, up to 75% of women with advanced disease will relapse at a median time of approximately 10 months.2

After recurrence, the duration of the platinum- free interval remains as the most important prognostic factor.3,4 Patients who relapse within 6 months of completing a platinum- based regimen are classified as platinum resistant, while those who relapse more than 6 months after treatment are classified as platinum sensitive.

Standard cytotoxic treatment for the latter group of patients includes a platinum-based regimen most frequently combined with paclitaxel,5 pegylated liposomal doxorubicin,6 or gemcitabine. 7 However, the duration of response to each subsequent platinum-based regimen tends to become progressively shorter and eventually patients become platinum resistant.

Many cytotoxic agents have been evaluated in phase II clinical trials in the platinum-resistant setting. Response rates are typically 20% or lower and durations of response are short. Docetaxel,8 weekly paclitaxel,9 pegylated liposomal doxorubicin,10 topotecan,11 gemcitabine,12 pemetrexed,13 and nab-paclitaxel14 are probably the most active and best-studied agents.

Only a few of these agents have been evaluated in phase III randomized trials.15-20 It can be concluded from these studies that topotecan, paclitaxel, weekly paclitaxel, pegylated liposomal doxorubicin, and gemcitabine have comparable activity.

Many other agents were studied before the use of modern chemotherapy regimens and, therefore, their true activity in today’s environment is unknown.21

Recently, etirinotecan pegol, an investigational topoisomerase I inhibitor, was reported to have encouraging activity in patients with heavily pretreated chemotherapy-resistant ovarian cancer.22 However, no further studies have been reported.

Angiogenesis Inhibitors

Bevacizumab

Several investigational cytotoxic agents were reported to have encouraging activity in phase II trials. However, phase III trials failed to demonstrate superiority over conventional agents.23-27 Indeed, no cytotoxic chemotherapy agent has been approved for the treatment of recurrent ovarian cancer since 2006.Nearly 20 years ago, it was reported that VEGF was overexpressed in human ovarian tumors and that it conferred a poor prognosis.28, 29 Similarly, it was observed that VEGF was directly associated with the development of ascites and carcinomatosis in animal models and that antibodies against VEGF inhibited tumor growth and ascites formation.30,31 These and other findings prompted researchers to evaluate the potential role of angiogenesis inhibitors in clinical trials in ovarian cancer.Bevacizumab is, by far, the most extensively studied agent in ovarian cancer. Single-arm phase II studies have demonstrated significant activity of bevacizumab as a single agent32,33 or in combination with low-dose metronomic chemotherapy.34

Despite the limitation of cross-comparison studies, the addition of low-dose oral cyclophosphamide appears to confer increased activity, as manifested by an impressive 6-month progression- free survival (PFS) with no significant increase in toxicity or cost. Several tyrosine kinase inhibitors have also been reported to have activity in recurrent ovarian cancer. However, they do not appear to have significant advantages over bevacizumab.35-39

Based on these results, several inhibitors of angiogenesis were evaluated in phase III randomized trials in combination with chemotherapy. Studies have been conducted in combination with chemotherapy in frontline therapy for the treatment of patients with platinum-sensitive and platinum-resistant disease, as well as in maintenance treatment.2,40-45

These studies have universally shown that the addition of bevacizumab to conventional chemotherapy improves response rate and PFS. However, improvements in overall survival have generally not been observed.

In November 2014, the FDA approved the use of bevacizumab in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for patients with platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.

The approval was based on an international two-arm trial that compared bevacizumab plus chemotherapy of physician’s choice versus chemotherapy alone. The trial included 361 patients with platinum-resistant disease that had progressed less than 6 months after the most recent therapy. The participants had received ≤2 prior chemotherapy regimens.46

Overall, the bevacizumab-containing regimens registered an improvement in median PFS of 6.8 months compared with 3.4 months for chemotherapy alone (HR, 0.38; P <.0001).46 Patients who received bevacizumab plus paclitaxel demonstrated the largest improvement, with a median PFS of 9.6 months versus 3.9 months for chemotherapy alone (HR, 0.47).

Trebananib

Although there was no statistically significant improvement in overall survival for the bevacizumab- containing arms, the findings suggested that patients who have received paclitaxel in an earlier round of therapy may benefit from bevacizumab plus weekly paclitaxel.46The angiopoietin (Ang)—Tie axis is composed of two cytokines, Ang 1 and Ang 2, which regulate angiogenic pathways in late stages of neovascularization. These interact with the Tie2 receptor to mediate vascular remodeling. Ang 1 predominantly stabilizes endothelial junctions and increases pericyte coverage while Ang2 promotes endothelial sprouting and increases blood vessel density.47-49

Trebananib (AMG 386) is an investigational recombinant peptide-Fc fusion protein that binds and neutralizes Ang 1 and Ang 2.50 Responses were observed in patients with ovarian cancer in a phase I study.51 A dose-dependent prolongation in PFS was observed when combined with paclitaxel in a randomized phase II study.52

However, only modest activity was observed when trebananib was evaluated as a single agent.53 Overall, the agent is well tolerated, with fluid retention as its most common dose-limiting toxicity. These findings led to the development of randomized phase III trials for trebananib as frontline therapy and in the setting of platinumsensitive and -resistant disease.

PARP Inhibitors

Olaparib

Patients with recurrent ovarian cancer and a platinum-free interval of less than 12 months were enrolled in a phase III trial using the addition of trebananib to weekly paclitaxel. This treatment resulted in a significant improvement in response rate and PFS (primary endpoint). Although no differences were observed in overall survival, a subset analysis suggested a benefit in those patients with ascites present at baseline. 54,55 Results from additional phase III trials are expected.Poly (ADP-ribose) polymerase (PARP) is an enzyme involved in base excision repair, a key mechanism in the repair of DNA single-strand breaks.56 BRCA-deficient cells appear to be particularly susceptible to the effects of these drugs.57Olaparib is the PARP inhibitor that has been Strategic Alliance Partnership Program studied most extensively.58 It inhibits several isoforms of PARP. Olaparib inhibits tumor growth of various cell lines and decreases tumor growth in xenograft models. Increased efficacy was documented in BRCA-deficient cell lines.

Several clinical trials of PARP inhibitors, predominantly evaluating patients with BRCA germline mutations, have been reported.59-63 Significant activity was reported in all of these studies, including early phase I trials.

In December 2014, the FDA approved olaparib for the treatment of recurrent ovarian cancer. This was approved for use in patients with a deleterious or suspected deleterious germline BRCA mutation who have been previously treated with three or more prior lines of therapy. This approval was based on an international, multicenter, single-arm trial that enrolled 298 patients with a deleterious or suspected deleterious BRCA mutation. This included 193 women with ovarian cancer, 137 of whom had measurable disease.62

Olaparib was administered at a dose of 400 mg orally until disease progression or toxicity. The median number of prior chemotherapy regimens was five. The overall response rate was 34%, with a median duration of response of 7.9 months and a median PFS of 7 months.

The most commonly observed adverse events were fatigue (66%), nausea (64%), vomiting (43%), diarrhea (31%), and anemia (34%). However, toxicities of grade 3-4 severity were uncommon and were observed for the most frequently observed adverse events in 8%, 3%, 4%, 1%, and 18% of patients, respectively.

The activity of olaparib according to platinum resistance has only been evaluated in one small study that enrolled 37 women. A response rate of 46% was observed among 13 women with platinum-sensitive disease while the response among 24 women with platinum-resistant ovarian cancer was 33%.

Veliparib

Rucaparib

Another small study included women with and without a BRCA mutation. The response rates were 41% and 24%, respectively.The efficacy of veliparib was reported in a phase II trial of 50 women with a known BRCA germline mutation.64 Patients had received up to three prior chemotherapy regimens. Veliparib was administered orally at a dose of 400 mg twice a day. The overall response rate was 26%. The response among 20 patients with platinum-sensitive disease was 35%, while among 30 women with resistant disease, the response was 20%. Overall PFS was 8.1 months.Rucaparib was evaluated among 35 women with a germline BRCA mutation and platinum sensitive ovarian cancer.65 The number of prior chemotherapy regimens was two. Overall response rate was 66%.

As a group, these studies show that PARP inhibitors have significant activity in recurrent ovarian cancer. Activity is well documented in patients with a BRCA germline mutation, and early findings suggest that this activity persists in high-grade serous ovarian tumors. Preliminary studies suggest a role when used as maintenance therapy, and confirmatory studies are ongoing.66

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015 [published online January 5, 2015]. CA Cancer J Clin. 2015;65(1)5—29.
  2. Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365(26):2473-2483.
  3. Markman M, Hoskins W. Responses to salvage chemotherapy in ovarian cancer: a critical need for precise definitions of the treated population. J Clin Oncol. 1992;10(4):513-514.
  4. Eisenhauer EA, Vermorken JB, van Glabbeke M. Predictors of response to subsequent chemotherapy in platinum pretreated ovarian cancer: a multivariate analysis of 704 patients. Ann Oncol. 1997;8(10):963-968.
  5. Parmar MK, Ledermann JA, Colombo N, et al. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet. 2003;361(9375):2099—2106.
  6. Pujade-Lauraine E, Wagner U, Aavall-Lundqvist E, et al. Pegylated liposomal doxorubicin and carboplatin compared with paclitaxel and carboplatin for patients with platinum-sensitive ovarian cancer in late relapse [published online May 24, 2010]. J Clin Oncol. 2010;28(20):3323—3329.
  7. Pfisterer J, Plante M, Vergote I, et al. Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol. 2006; 24:4699—4707.
  8. Rose PG, Blessing JA, Ball HG, et al. A phase II study of docetaxel in paclitaxel-resistant ovarian and peritoneal carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2003; 88:130-135.
  9. Markman M, Hall J, Spitz D, et al. Phase II trial of weekly single-agent paclitaxel in platinum/paclitaxel-refractory ovarian cancer. J Clin Oncol. 2002; 20:2365-2369.
  10. Muggia FM, Hainsworth JD, Jeffers S, et al: Phase II study of liposomal doxorubicin in refractory ovarian cancer: antitumor activity and toxicity modification by liposomal encapsulation. J Clin Oncol. 1997; 15:987-993.
  11. Bookman MA, Malmstrom H, Bolis G, et al: Topotecan for the treatment of advanced epithelial ovarian cancer: an open-label phase II study in patients treated after prior chemotherapy that contained cisplatin or carboplatin and paclitaxel. J Clin Oncol. 1998;16:3345-3352.
  12. Shapiro JD, Millward MJ, Rischin D, et al: Activity of gemcitabine in patients wih advanced ovarian cancer: responses seen following platinum and paclitaxel. Gyn Oncol. 1996;63:89-93.
  13. Miller DS, Blessing JA, Krasner CN, et al. Phase II evaluation of pemetrexed in the treatment of recurrent or persistent platinum-resistant ovarian or primary peritoneal carcinoma: a study of the Gynecologic Oncology Group. J Clin Oncol. 2009;27:2686-2691.
  14. Coleman RL, Brady WE, McMeekin DS, et al. A phase II evaluation of nanoparticle, albumin-bound (nab) paclitaxel in the treatment of recurrent or persistent platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer: a Gynecologic Oncology Group study. Gynecol Oncol. 2011;122:111-115.
  15. ten Bokkel Huinink W, Gore M, Carmichael J, et al: Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. J Clin Oncol 1997;15:2183-2193.
  16. Rosenberg P, Andersson H, Boman K, et al. Randomized trial of single agent paclitaxel given weekly versus every three weeks and with peroral versus intravenous steroid premedication to patients with ovarian cancer previously treated with platinum. Acta Oncol. 2002;41:418-424.
  17. Gordon AN, Fleagle JT, Guthrie D, et al. Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol. 2001; 19: 3312-3322.
  18. O’Byrne KJ, Bliss P, Graham JD, et al. A phase III study of Doxil/Caylex versus paclitaxel in platinum treated taxane naive relapsed ovarian cancer. Proc Am Soc Clin Oncol. 2002;21:203a.
  19. Mutch DG, Orlando M, Goss T, et al. Randomized phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer. J Clin Oncol. 2007;25:2811-2818.
  20. Ferrandina G, Ludovisi M, Lorusso D, et al. Phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in progressive or recurrent ovarian cancer. J Clin Oncol. 2008; 26:890-896.
  21. Garcia AA. Salvage therapy for ovarian cancer. Curr Oncol Rep. 1999;1(1): 64-70.
  22. Vergote IB, Garcia A, Micha J, et al. Randomized multicenter phase II trial comparing two schedules of etirinotecan pegol (NKTR-102) in women with recurrent platinum-resistant/refractory epithelial ovarian cancer. J Clin Oncol. 2013;31(32):4060-4066.
  23. Kavanagh JJ, Gershenson DM, Choi H, et al. Multi-institutional phase 2 study of TLK286 (TELCYTA, a glutathione S-transferase P1-1 activated glutathione analog prodrug) in patients with platinum and paclitaxel refractory or resistant ovarian cancer. Int J Gynecol Cancer. 2005; 15(4):593-600.
  24. Krasner CN, McMeekin DS, Chan S, et al. A phase II study of trabectedin single agent in patients with recurrent ovarian cancer previously treated with platinum-based regimens. Br J Cancer. 2007;97:1618-1624.
  25. Meier W, du Bois A, Reuss A, et al. Topotecan versus treosulfan, an alkylating agent, in patients with epithelial ovarian cancer and relapse within 12 months following 1st-line platinum/paclitaxel chemotherapy. A prospectively randomized phase III trial by the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group (AGO-OVAR). Gynecol Oncol. 2009;114:199-205.
  26. Vergote I, Finkler NJ, Hall JB, et al. Randomized phase III study of canfosfamide in combination with pegylated liposomal doxorubicin compared with pegylated liposomal doxorubicin alone in platinum-resistant ovarian cancer. Int J Gynecol Cancer. 2010; 20:772-780.
  27. Monk BJ, Herzog TJ, Kaye SB, et al. Trabectedin plus pegylated liposomal Doxorubicin in recurrent ovarian cancer. J Clin Oncol. 2010;28:3107-3114.
  28. Yoneda J, Kuniyasu H, Crispens MA, et al: Expression of angiogenesis related genes and progression of human ovarian carcinomas in nude mice. J Natl Cancer Inst. 1998;90:447-454.
  29. Abu-Jawdeh GM, Faix JD, Niloff J, et al: Strong expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in ovarian borderline and malignant neoplasms. Lab Invest. 1996;74:1105-1115.
  30. Yamamoto S, Konishi I, Mandai M, et al. Expression of vascular endothelial growth factor (VEGF) in epithelial ovarian neoplasms: correlation with clinicopathology and patient survival, and analysis of serum VEGF levels. Br J Cancer. 1997;76:1221-1227.
  31. Mesiano S, Ferrara N, Jaffe RB. Role of vascular endothelial growth factor in ovarian cancer: inhibition of ascites formation by immunoneutralization. Am J Pathol. 1998; 153:1249-1256.
  32. Burger RA, Sill MW, Monk BJ, et al. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a gynecologic oncology group study. J Clin Oncol. 2007;25:5165-5171.
  33. Cannistra SA, Matulonis UA, Penson RT, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol. 2007; 25:5180-5186.
  34. Garcia AA, Hirte H, Fleming G, et al. Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital phase II consortia. J Clin Oncol. 2008;26:76-82.
  35. Hirte H, Lheureux S, Fleming GF, et al. A phase II study of cediranib in recurrent or persistent ovarian, peritoneal or fallopian tube cancer: a trial of the Princess Margaret, Chicago and California phase II consortia. Gynecol Oncol. 2015;138:55-61.
  36. Friedlander M, Hancock KC, Rischin D, et al. A phase II, open-label study evaluating pazopanib in patients with recurrent ovarian cancer. Gynecol Oncol. 2010;119(1):32-37.
  37. Campos SM, Penson RT, Matulonis U, et al. A phase II trial of sunitinib malate in recurrent and refractory ovarian, fallopian tube and peritoneal carcinoma. Gynecol Oncol. 2013;128:215-220.
  38. Baumann KH, du Bois A, Meier W, et al. A phase II trial (AGO 2.11) in platinum-resistant ovarian cancer: a randomized multicenter trial with sunitinib (SU11248) to evaluate dosage, schedule, tolerability, toxicity and effectiveness of a multitargeted receptor tyrosine kinase inhibitor monotherapy. Ann Oncol. 2012;23:2265-2271.
  39. Biagi JJ, Oza AM, Chalchal HI, et al. A phase II study of sunitinib in patients with recurrent epithelial ovarian and primary peritoneal carcinoma: an NCIC clinical trials group study. Ann Oncol. 2011;22:335-340.
  40. Perren T, Swart A, Pfisterer J, et al. for the ICON7 Investigators (2011) A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 365: 2484—2496.
  41. Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012;30:2039-2045.
  42. du Bois A, Floquet A, Kim JW, et al. Incorporation of pazopanib in maintenance therapy of ovarian cancer. J Clin Oncol. 2014;32:3374-3382.
  43. Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Oncol. 2014;32:1302-1308.
  44. Du Bois, A, Kristensen, G, Ray-Coquard I, et al. AGO-OVAR 12: A randomized placebo-controlled GCIG/ENGOT-intergroup phase III trial of standard frontline chemotherapy +/- nintedanib for advanced ovarian cancer [abstract]. Int J Gyn Cancer. 2013; 23: PL01.
  45. Ledermann JA, Perren JG, Raja FA, et al. Randomised double-blind phase III trial of cediranib (AZD 2171) in relapsed platinum sensitive ovarian cancer: Results of the ICON6 trial. Eur J Cancer. 2013; 49 (Suppl 3): Abs 10.
  46. FDA approval for bevacizumab. National Cancer Institute website. http://www.cancer.gov/about-cancer/treatment/drugs/fda-bevacizumab#Anchor-Ovarian. Accessed September 30, 2015.
  47. Augustin HG, Koh GY, Thurston G, Alitalo K. Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol. 2009;10:165-177.
  48. Falcón BL, Hashizume H, Koumoutsakos P, et al. Contrasting actions of selective inhibitors of angiopoietin-1 and angiopoietin-2 on the normalization of tumor blood vessels. Am J Pathol. 2009;175:2159-2170.
  49. Scharpfenecker M, Fiedler U, Reiss Y, Augustin HG. The Tie-2 ligand angiopoietin-2 destabilizes quiescent endothelium through an internal autocrine loop mechanism. J Cell Sci. 2005;118(Pt 4):771-780.
  50. Liontos M, Lykka M, Dimopoulos MA, et al. Profile of trebananib (AMG386) and its potential in the treatment of ovarian cancer. Onco Targets Ther. 2014;7:1837-1845.
  51. Herbst RS, Hong D, Chap L, et al. Safety, pharmacokinetics, and antitumor activity of AMG 386, a selective angiopoietin inhibitor, in adult patients with advanced solid tumors. J Clin Oncol. 2009;27:3557-3565.
  52. Karlan BY, Oza AM, Richardson GE, et al. Randomized, double-blind, placebo-controlled phase II study of AMG 386 combined with weekly paclitaxel in patients with recurrent ovarian cancer. J Clin Oncol. 2012; 30:362-371.
  53. Moore KN, Sill MW, Tenney ME, Darus CJ, Griffin D, et al. A phase II trial of trebananib (AMG 386; IND#111071), a selective angiopoietin 1/2 neutralizing peptibody, in patients with persistent/recurrent carcinoma of the endometrium: An NRG/Gynecologic Oncology Group trial. Gynecol Oncol. 2015;138(3):513-518.
  54. Monk BJ, Poveda A, Vergote I, et al. Anti-angiopoietin therapy with trebananib for recurrent ovarian cancer (TRINOVA-1): a randomised, multicentre, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2014;15:799-808.
  55. Monk BJ, Poveda A, Vergote I, et al. Impact of trebananib plus weekly paclitaxel on overall survival (OS) in patients (pts) with recurrent ovarian cancer and ascites: Results from the phase III TRINOVA-1 study. J Clin Oncol. 33, 2015 (suppl; abstr 5503).
  56. Helleday T, Bryant HE, Schultz N. Poly(ADP-ribose) polymerase (PARP-1) in homologous recombination and as a target for cancer therapy. Cell Cycle. 2005; 4:1176-1178.
  57. Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434:917-921.
  58. Kim G, Ison G, McKee AE, et al. FDA approval summary: olaparib monotherapy in patients with deleterious germline BRCA-mutated advanced ovarian cancer treated with three or more lines of chemotherapy. Clin Cancer Res. 2015;21(19):4257-4261.
  59. Fong PC, Boss DS, Yap TA, Tutt A, Wu P,et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361:123-134.
  60. Fong PC, Yap TA, Boss DS, et al. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol. 2010;28:2512-2519.
  61. 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. 2012;30(4):372-379.
  62. 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. 2015;33(3):244-250.
  63. 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. 2010;376(9737):245-251.
  64. Coleman RL, Sill MW, Bell-McGuinn K, et al. A phase II evaluation of the potent, highly selective PARP inhibitor veliparib in the treatment of persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who carry a germline BRCA1 or BRCA2 mutation - An NRG Oncology/Gynecologic Oncology Group study. Gynecol Oncol. 2015;137(3):386-391.
  65. Ronnie Shapira-Frommer, Amit M. Oza, Susan M. Domchek, et al. A phase II open-label, multicenter study of single-agent rucaparib in the treatment of patients with relapsed ovarian cancer and a deleterious BRCA mutation. J Clin Oncol 33, 2015 (suppl; abstr 5513).
  66. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366(15):1382-1392.