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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

      Highlights

      • Veliparib has single-agent activity among germline BRCA1/2 mutation carriers.
      • Adverse events were observed but generally mild and managed conservatively.
      • Responses were observed among platinum-sensitive and -resistant recurrent disease patients.

      Abstract

      Background

      Veliparib is a potent small molecule inhibitor of PARP-1/2, which is cytotoxic in tumor cells with deficiencies in BRCA1 or BRCA2. We studied the clinical activity and toxicity of veliparib in ovarian cancer patients carrying a germline BRCA1 or BRCA2 mutation (gBRCA).

      Methods

      Eligibility included three or fewer prior chemotherapy regimens, measurable disease and no prior use of a PARP inhibitor. Veliparib was administered at 400 mg orally BID with one cycle being 28 days. The two-stage Simon design was capable of detecting a 25% response probability with 90% power while controlling alpha = 10% (at a 10% assumed null response probability).

      Results

      The median age of the 50 eligible patients was 57 years (range 37–94) and 14, 18, and 18 patients had 1, 2, and 3 prior therapies respectively. Thirty patients (60%) were platinum-resistant. The median number of cycles administered was 6 (1–27). There was one grade 4 thrombocytopenia. Grade 3 adverse events were: fatigue (n = 3), nausea (2), leukopenia (1), neutropenia (1), dehydration (1), and ALT (1). Grade 2 events >10% were: nausea (46%), fatigue (26%), vomiting (18%), and anemia (14%). The proportion responding was 26% (90% CI: 16%–38%, CR: 2, PR: 11); for platinum-resistant and platinum-sensitive patients the proportion responding was 20% and 35%, respectively. The most common reason for treatment discontinuation was progression (62%). Twenty-nine patients are alive; two with SD remain on veliparib. The median PFS is 8.18 months.

      Conclusions

      The single agent efficacy and tolerability of veliparib for BRCA mutation-associated recurrent ovarian cancer warrants further investigation.

      Keywords

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      References

        • Bridges C.B.
        The origin of variation.
        Am. Nat. 1922; 56: 51-63
        • Dobzhansky T.
        Genetics of natural populations. XIII. Recombination and variability in populations of Drosophila pseudoobscura.
        Genetics. 1946; 31: 269-290
        • Hartwell L.H.
        • Szankasi P.
        • Roberts C.J.
        • et al.
        Integrating genetic approaches into the discovery of anticancer drugs.
        Science. 1997; 278: 1064-1068
        • Banerjee S.
        • Kaye S.B.
        • Ashworth A.
        Making the best of PARP inhibitors in ovarian cancer.
        Nat. Rev. Clin. Oncol. 2010; 7: 508-519
        • Bajrami I.
        • Frankum J.R.
        • Konde A.
        • et al.
        Genome-wide profiling of genetic synthetic lethality identifies CDK12 as a novel determinant of PARP1/2 inhibitor sensitivity.
        Cancer Res. 2014; 74: 287-297
        • Jervis S.
        • Song H.
        • Lee A.
        • et al.
        Ovarian cancer familial relative risks by tumour subtypes and by known ovarian cancer genetic susceptibility variants.
        J. Med. Genet. 2014; 51: 108-113
        • Bryant H.E.
        • Schultz N.
        • Thomas H.D.
        • et al.
        Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.
        Nature. 2005; 434: 913-917
        • Farmer H.
        • McCabe N.
        • Lord C.J.
        • et al.
        Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.
        Nature. 2005; 434: 917-921
        • Patel A.G.
        • Sarkaria J.N.
        • Kaufmann S.H.
        Nonhomologous end joining drives poly(ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells.
        Proc. Natl. Acad. Sci. U. S. A. 2011; 108: 3406-3411
        • Fong P.C.
        • Boss D.S.
        • Yap T.A.
        • et al.
        Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers.
        N. Engl. J. Med. 2009; 361: 123-134
        • Ledermann J.
        • Harter P.
        • Gourley C.
        • et al.
        Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer.
        N. Engl. J. Med. 2012; 366: 1382-1392
        • Kaye S.B.
        • 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: 372-379
        • Oza A.
        • Cibula D.
        • Benzaquen A.
        • et al.
        Olaparib plus paclitaxel and carboplatin followed by olaparib maintenance treatment in patients with platinum-sensitive recurrent serous ovarian cancer: a randomized, open-label Phase II study.
        J. Clin. Oncol. 2012; 30: 5001
        • Gelmon K.A.
        • Tischkowitz M.
        • Mackay H.
        • et al.
        Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study.
        Lancet Oncol. 2011; 12: 852-861
        • Sandhu S.K.
        • Schelman W.R.
        • Wilding G.
        • et al.
        The poly (ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial.
        Lancet Oncol. 2013; 14: 882-892
        • Donawho C.K.
        • Luo Y.
        • Luo Y.
        • et al.
        ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models.
        Clin. Cancer Res. 2007; 13: 2728-2737
      1. Positive results for drug combo veliparib in I-SPY 2 trial.
        Cancer Discov. 2014; 4 (Epub 2014 Jan 9, No authors listed): OF2
        • Kummar S.
        • Ji J.
        • Morgan R.
        • et al.
        A phase I study of veliparib in combination with metronomic cyclophosphamide in adults with refractory solid tumors and lymphomas.
        Clin. Cancer Res. 2012; 18: 1726-1734
        • Kummar S.
        • Chen A.
        • Ji J.
        • et al.
        Phase I study of PARP inhibitor ABT-888 in combination with topotecan in adults with refractory solid tumors and lymphomas.
        Cancer Res. 2011; 71: 5626-5634
      2. Veliparib plus temozolomide in metastatic melanoma trends toward increased PFS but results are not statistically significant.
        Oncology (Williston Park). 2011; 25: 1213-1232
        • Eisenhauer E.A.
        • Therasse P.
        • Bogaerts J.
        • et al.
        New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
        Eur. J. Cancer. 2009; 45: 228-247
        • Chen T.T.
        • Ng T.H.
        Optimal flexible designs in phase II clinical trials.
        Stat. Med. 1998; 17: 2301-2312
        • Audeh M.W.
        • Carmichael J.
        • Penson R.T.
        • 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: 245-251
        • Sill M.
        Adapting rejection boundaries when the targeted accrual is not attained in 2-stage phase II clinical trials.
        in: Technical Report 04-01. University at Buffalo, 2001
        • Kaplan E.
        • Meier P.
        Nonparametric estimation from incomplete observations.
        J. Am. Stat. Assoc. 1958; 53: 457-481
        • Bryant C.S.
        • Kumar S.
        • Spannuth W.
        • et al.
        Feasibility of extension of platinum-free interval with weekly bolus topotecan and subsequent platinum retreatment outcomes in recurrent ovarian cancer.
        Arch. Gynecol. Obstet. 2011; 283: 361-367
        • Ledermann J.A.
        Benefits of enhancing the platinum-free interval in the treatment of relapsed ovarian cancer: more than just a hypothesis?.
        Int. J. Gynecol. Cancer. 2011; 21: S9-S11
        • Yang D.
        • Khan S.
        • Sun Y.
        • et al.
        Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer.
        JAMA. 2011; 306: 1557-1565
        • Lee J.M.
        • Ledermann J.A.
        • Kohn E.C.
        PARP Inhibitors for BRCA1/2 mutation-associated and BRCA-like malignancies.
        Ann. Oncol. 2014; 25: 32-40
        • Hennessy B.T.
        • Timms K.M.
        • Carey M.S.
        • et al.
        Somatic mutations in BRCA1 and BRCA2 could expand the number of patients that benefit from poly (ADP ribose) polymerase inhibitors in ovarian cancer.
        J. Clin. Oncol. 2010; 28: 3570-3576
        • Pennington K.P.
        • Walsh T.
        • Harrell M.I.
        • 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. 2014; 20: 764-775
        • Stordal B.
        • Timms K.
        • Farrelly A.
        • et al.
        BRCA1/2 mutation analysis in 41 ovarian cell lines reveals only one functionally deleterious BRCA1 mutation.
        Mol. Oncol. 2013; 7: 567-579
        • Lord C.J.
        • Ashworth A.
        Mechanisms of resistance to therapies targeting BRCA-mutant cancers.
        Nat. Med. 2013; 19: 1381-1388
        • Edwards S.L.
        • Brough R.
        • Lord C.J.
        • et al.
        Resistance to therapy caused by intragenic deletion in BRCA2.
        Nature. 2008; 451: 1111-1115
        • Norquist B.
        • Wurz K.A.
        • Pennil C.C.
        • et al.
        Secondary somatic mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian carcinomas.
        J. Clin. Oncol. 2011; 29: 3008-3015
        • Sakai W.
        • Swisher E.M.
        • Karlan B.Y.
        • et al.
        Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers.
        Nature. 2008; 451: 1116-1120
        • Bunting S.F.
        • Callen E.
        • Wong N.
        • et al.
        53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks.
        Cell. 2010; 141: 243-254
        • Bunting S.F.
        • Callen E.
        • Kozak M.L.
        • et al.
        BRCA1 functions independently of homologous recombination in DNA interstrand crosslink repair.
        Mol. Cell. 2012; 46: 125-135
        • Rottenberg S.
        • Jaspers J.E.
        • Kersbergen A.
        • et al.
        High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs.
        Proc. Natl. Acad. Sci. U. S. A. 2008; 105: 17079-17084
        • Murai J.
        • Huang S.Y.
        • Das B.B.
        • et al.
        Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors.
        Cancer Res. 2012; 72: 5588-5599
        • Kaufman B.
        • Shapira-Frommer R.
        • Schmutzler R.K.
        • et al.
        Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation.
        J. Clin. Oncol. 2015; 33: 244-250