Phase I/Ib study of olaparib and carboplatin in heavily pretreated recurrent high-grade serous ovarian cancer at low genetic risk

Purpose: To investigate maximum tolerated dose (MTD), activity and predictive biomarkers of olaparib with carboplatin in BRCA wild-type (BRCAwt) high grade serous ovarian carcinoma (HGSOC) patients. Methods: A 3+3 dose escalation study examined olaparib capsules (400 mg twice daily [BID], days 1–7) with carboplatin (AUC3-5 on day 1) every 21 days for 8 cycles, followed by olaparib 400 mg BID maintenance. Blood and tumor biopsy samples were collected pre- and on-treatment in the expansion cohort for PAR levels and proteomic endpoints. Results: 30 patients (median 7 prior regimens [2–12], 63% (19/30) platinum-resistant) were enrolled. Dose-limiting toxicity was thrombocytopenia/neutropenia, and infection with carboplatin AUC5 (2/6 patients). MTD was olaparib 400 mg BID + carboplatin AUC4. Grade 3/4 adverse events (>10%) included neutropenia (23%), thrombocytopenia (20%), and anemia (13%). Five of 25 (20%) evaluable patients had partial response (PR; median 4.5 months [3.3–9.5]). Clinical benefit rate (PR + stable disease ≥4 months) was 64% (16/25). A greater decrease in tissue PAR levels was seen in the clinical benefit group versus no benefit (median normalized linear change −1.84 [−3.39– −0.28] vs 0.51 [−0.27– 1.29], p = 0.001) and a DNA repair score by proteomics did not correlate with response. Conclusions: The olaparib and carboplatin combination is tolerable and has clinical benefit in subsets of heavily pretreated BRCAwt HGSOC, independent of platinum sensitivity.

[1]  J. Webber.  Center , 2011 .

[2]  Gabe S. Sonke,et al.  Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer , 2018, The New England journal of medicine.

[3]  W. Vermeulen,et al.  Base and nucleotide excision repair facilitate resolution of platinum drugs-induced transcription blockage , 2018, Nucleic acids research.

[4]  S. Pignata,et al.  Latest clinical evidence and further development of PARP inhibitors in ovarian cancer , 2018, Annals of oncology : official journal of the European Society for Medical Oncology.

[5]  A. Jemal,et al.  Ovarian cancer statistics, 2018 , 2018, CA: a cancer journal for clinicians.

[6]  G. Zafarana,et al.  BRCA Status Does Not Predict Synergism of a Carboplatin and Olaparib Combination in High-Grade Serous Ovarian Cancer Cell Lines. , 2018, Molecular pharmaceutics.

[7]  James X. Sun,et al.  Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial , 2017, The Lancet.

[8]  Val Gebski,et al.  Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. , 2017, The Lancet. Oncology.

[9]  E. Kohn,et al.  Phase I/Ib study of olaparib and carboplatin in women with triple negative breast cancer , 2017, Oncotarget.

[10]  Alan Ashworth,et al.  PARP inhibitors: Synthetic lethality in the clinic , 2017, Science.

[11]  Anne Floquet,et al.  Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. , 2017, The Lancet. Oncology.

[12]  Ignace Vergote,et al.  Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. , 2016, The New England journal of medicine.

[13]  E. Kohn,et al.  Sequence-Specific Pharmacokinetic and Pharmacodynamic Phase I/Ib Study of Olaparib Tablets and Carboplatin in Women's Cancer , 2016, Clinical Cancer Research.

[14]  Y. Drew,et al.  Homologous recombination deficiency and ovarian cancer. , 2016, European journal of cancer.

[15]  Gordon B Mills,et al.  New era of integrated cancer biomarker discovery using reverse-phase protein arrays. , 2016, Drug metabolism and pharmacokinetics.

[16]  G. Shapiro,et al.  Homologous Recombination Deficiency: Exploiting the Fundamental Vulnerability of Ovarian Cancer. , 2015, Cancer discovery.

[17]  Yulong He,et al.  Combined olaparib and oxaliplatin inhibits tumor proliferation and induces G2/M arrest and γ-H2AX foci formation in colorectal cancer , 2015, OncoTargets and therapy.

[18]  Joshy George,et al.  Whole–genome characterization of chemoresistant ovarian cancer , 2015, Nature.

[19]  Ayala Hubert,et al.  Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  H. Mackay,et al.  Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial. , 2015, The Lancet. Oncology.

[21]  D. Matei,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 , 2014 .

[22]  E. Winer,et al.  Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors. , 2014, Annals of oncology : official journal of the European Society for Medical Oncology.

[23]  Lori Minasian,et al.  Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses. , 2014, Journal of the National Cancer Institute.

[24]  Sheena M. Scroggins,et al.  Germline and Somatic Mutations in Homologous Recombination Genes Predict Platinum Response and Survival in Ovarian, Fallopian Tube, and Peritoneal Carcinomas , 2013, Clinical Cancer Research.

[25]  Ying Feng,et al.  Proteomic Markers of DNA Repair and PI3K Pathway Activation Predict Response to the PARP Inhibitor BMN 673 in Small Cell Lung Cancer , 2013, Clinical Cancer Research.

[26]  H. Wildiers,et al.  Phase I trial of the oral PARP inhibitor olaparib in combination with paclitaxel for first- or second-line treatment of patients with metastatic triple-negative breast cancer , 2013, Breast Cancer Research.

[27]  A. Jager,et al.  Phase I study of olaparib in combination with carboplatin and/or paclitaxel in patients with advanced solid tumors. , 2013 .

[28]  E. Kohn,et al.  Feasibility and safety of sequential research‐related tumor core biopsies in clinical trials , 2013, Cancer.

[29]  P. Meltzer,et al.  Translational Predictive Biomarker Analysis of the Phase 1b Sorafenib and Bevacizumab Study Expansion Cohort* , 2013, Molecular & Cellular Proteomics.

[30]  Gordon B Mills,et al.  Proteomic classification of breast cancer. , 2012, Current drug targets.

[31]  J. Brenton,et al.  Evolution of platinum resistance in high-grade serous ovarian cancer. , 2011, The Lancet. Oncology.

[32]  H. Mackay,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. , 2011, The Lancet. Oncology.

[33]  Benjamin J. Raphael,et al.  Integrated Genomic Analyses of Ovarian Carcinoma , 2011, Nature.

[34]  Eric P Kaldjian,et al.  Upregulation of Poly (ADP-Ribose) Polymerase-1 (PARP1) in Triple-Negative Breast Cancer and Other Primary Human Tumor Types. , 2010, Genes & cancer.

[35]  Thomas J. Hardcastle,et al.  Genomic analysis of genetic heterogeneity and evolution in high-grade serous ovarian carcinoma , 2010, Oncogene.

[36]  Jan Lubinski,et al.  Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  I. Vergote,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 , 2010, International Journal of Gynecologic Cancer.

[38]  J. Thigpen.  High Poly(Adenosine Diphosphate-Ribose) Polymerase Expression and Poor Survival in Advanced-Stage Serous Ovarian Cancer , 2010 .

[39]  R. Schilder,et al.  Management of recurrent ovarian carcinoma: current status and future directions. , 2009, Seminars in oncology.

[40]  L. Rubinstein,et al.  Preclinical Modeling of a Phase 0 Clinical Trial: Qualification of a Pharmacodynamic Assay of Poly (ADP-Ribose) Polymerase in Tumor Biopsies of Mouse Xenografts , 2008, Clinical Cancer Research.

[41]  F. Tramontano,et al.  Poly(ADPR)polymerase inhibition and apoptosis induction in cDDP-treated human carcinoma cell lines. , 2008, Biochemical pharmacology.

[42]  A. Ashworth,et al.  DNA repair deficiency as a therapeutic target in cancer. , 2008, Current opinion in genetics & development.

[43]  J. Thigpen.  Randomized Phase III Trial of Gemcitabine Compared With Pegylated Liposomal Doxorubicin in Patients With Platinum-Resistant Ovarian Cancer , 2008 .

[44]  Howard Mackey,et al.  Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[45]  Stephen J Lippard,et al.  Direct cellular responses to platinum-induced DNA damage. , 2007, Chemical reviews.

[46]  Thomas Helleday,et al.  Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase , 2007, Nature.

[47]  T. Herzog,et al.  Ovarian cancer: a focus on management of recurrent disease , 2006, Nature Clinical Practice Oncology.

[48]  Alan Ashworth,et al.  Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. , 2006, Cancer research.

[49]  S. Waggoner,et al.  Phase II trial of weekly paclitaxel (80 mg/m2) in platinum and paclitaxel-resistant ovarian and primary peritoneal cancers: a Gynecologic Oncology Group study. , 2006, Gynecologic oncology.

[50]  M. Fuertes,et al.  Poly(ADP-ribose) polymerase-1 inhibitor 3-aminobenzamide enhances apoptosis induction by platinum complexes in cisplatin-resistant tumor cells. , 2006, Medicinal chemistry (Shariqah (United Arab Emirates)).

[51]  J. Krischer,et al.  BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases , 2005, Cancer.

[52]  Alan Ashworth,et al.  Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy , 2005, Nature.

[53]  D. Mutch,et al.  The role of topotecan for extending the platinum-free interval in recurrent ovarian cancer: an in vitro model. , 2004, Gynecologic oncology.

[54]  W. Zeller,et al.  Reversal of acquired cisplatin resistance by nicotinamide in vitro and in vivo , 2004, Cancer Chemotherapy and Pharmacology.

[55]  T. Yano,et al.  Role of poly(ADP-ribose)polymerase in cisplatin-induced injury in LLC-PK1 cells. , 2003, Free radical biology & medicine.

[56]  B. Ruggeri,et al.  Chemopotentiation of temozolomide, irinotecan, and cisplatin activity by CEP-6800, a poly(ADP-ribose) polymerase inhibitor. , 2003, Molecular cancer therapeutics.

[57]  P. Rose,et al.  Gemcitabine reverses cisplatin resistance: demonstration of activity in platinum- and multidrug-resistant ovarian and peritoneal carcinoma. , 2003, Gynecologic oncology.

[58]  Giovanni Parmigiani,et al.  BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[59]  D Guthrie,et al.  Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[60]  A Gordon,et al.  Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[61]  A. Kudelka,et al.  Carboplatin reinduction after taxane in patients with platinum-refractory epithelial ovarian cancer. , 1995, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[62]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[63]  A. Bürkle,et al.  Increased poly(ADP-ribosyl)ation in intact cells by cisplatin treatment. , 1993, Carcinogenesis.