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Reply to M.G. McNamara et al and M.S. Copur et al

Publication: Journal of Clinical Oncology
We thank the authors for their supportive comments and questions regarding our study, “Olaparib Monotherapy in Patients With Advanced Cancer and Germline BRCA1/2 Mutations.”1
McNamara et al2 question the study design, end points, and dose modifications. This was a signal-seeking phase II study of olaparib with the inherent limitations of all phase II trials. The impact of olaparib on overall survival as well as on patient-reported outcomes such as symptom benefit is best addressed in randomized phase III trials. The primary aim of this trial was to look for an efficacy signal in heavily pretreated patients with germline BRCA mutations and a wide range of cancers that included ovarian, breast, pancreatic, and prostate, as well as others. These patients typically have limited treatment options and the results of phase II trials can drive progress. Indeed, the results of this study were included in the consideration by the US Food and Drug Administration for the approval of olaparib for women with BRCA-associated recurrent ovarian cancer after more than three lines of therapy (an unmet clinical need).
McNamara et al2 also question the dose modifications for toxicity and whether patients received adequate dose intensity. Future studies are needed to determine minimally effective dose. This is particularly relevant in patients who have been heavily pretreated who may be at risk of increased toxicities and require dose reductions.
We agree that knowledge of poststudy treatment after olaparib would be helpful. Approximately 50% of individuals overall (40% with pancreatic cancer) received subsequent therapy but detailed information is not available. McNamara et al2 ask whether an undiscovered PALB2 mutation could have contributed to hematologic adverse events. We think that this is unlikely given the rarity of coexistent homologous recombination (HR) gene mutations in BRCA mutation carriers and it is more likely that prior chemotherapy contributed to the toxicity seen.3
Copur et al4 asked about the impact on response rates of women with platinum-sensitive ovarian cancer who could not receive further platinum. Unfortunately, these data were not collected prospectively but are being retrospectively ascertained. A preliminary analysis suggests that approximately 70% had platinum-resistant/-refractory ovarian cancer. Once all data are available, we will report the response rates in ovarian patient by platinum status as well as address the percentage of patients with high-grade serous cancer. It is however likely that the majority had high-grade serous ovarian cancer in keeping with the literature.
Although not reported in the original article, an equal number of patients with breast cancer had estrogen receptor (ER) –positive and ER-negative disease (each group with 31, 50%). Four patients in each group had a confirmed RECIST partial response. This is consistent with data from Tutt et al,5 who did not observe difference in response rates to olaparib based on ER status.
Copur et al4 suggests that platinum sensitivity alone may be more important than BRCA status to predict response to poly(ADP–ribose) polymerase inhibitors, but this is not supported by the literature. There are certainly data that that platinum sensitivity is an important predictor of response to olaparib in patients with BRCA1/2 germline mutation-associated ovarian cancer, but responses have been previously reported in patients with BRCA-related platinum-resistant ovarian cancer.6,7 Gelmon et al8 reported that patients with BRCA-related recurrent ovarian cancer had a higher response to olaparib compared with platinum-sensitive wild-type ovarian cancer. In addition in the maintenance trial of olaparib versus placebo which included women with platinum-sensitive relapsed ovarian cancer, those with BRCA mutations had a significantly longer progression-free survival than patients with BRCA wild type.9
Both groups raise the pertinent question of whether the findings in this study could be applied to patients with germline mutations in other HR genes or in tumors with somatic mutations. This is an important and active area of research. Swisher et al10 recently presented the results of a study of rucaparib in recurrent ovarian cancer which found a response rate of over 60% in patients with BRCA mutations but importantly a response rate of over 30% in patients with high genomic loss of heterozygosity in their tumors. Pennington et al11 have reported that germline and somatic mutations in HR genes predict platinum response in ovarian cancer (although the number of mutations in non-BRCA1/2 HR genes was small). Clinical trials are in progress to address these important questions. These studies will also help inform the clinical utility, from a therapeutic perspective, of the use of multigene panel tests to identify patients most likely to benefit from treatment with a poly(ADP–ribose) polymerase inhibitor.

Authors' Disclosures of Potential Conflicts of Interest

Disclosures provided by the authors are available with this article at www.jco.org.

References

1.
B Kaufman, R Shapira-Frommer, RK Schmutzler, etal: Olaparib monotherapy in patients with advanced cancer and a germ-line BRCA1/2 mutation J Clin Oncol 33: 244– 250,2015
2.
MG McNamara, A Lamarca, RA Hubner, etal: To BRCA or not to PALB J Clin Oncol 33: 2581– 2582,2015
3.
C Turnbull, S Seal, A Renwick, etal: Gene-gene interactions in breast cancer susceptibility Hum Mol Genet 21: 958– 962,2012
4.
MS Copur, D Gauchan, K Brussow, etal: Germline BRCA1/2 mutations: Are they good enough to determine who will respond to poly(ADP–ribose) polymerase inhibitor therapy in advanced cancer? J Clin Oncol 33: 2582,2015
5.
A Tutt, M Robson, JE Garber, etal: Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA 2 mutations and advanced breast cancer: A proof-of-concept trial Lancet 376: 235– 244,2010
6.
PC Fong, TA Yap, DS Boss, etal: Poly(ADP)-ribose polymerase inhibition: Frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval J Clin Oncol 28: 2512– 2519,2010
7.
MW Audeh, J Carmichael, RT Penson, etal: 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
8.
KA Gelmon, M Tischkowitz, H Mackay, etal: 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 12: 852– 861,2011
9.
J Ledermann, P Harter, C Gourley, etal: 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
10.
E Swisher, J Brenton, S Kaufmann, etal: ARIEL2: A phase 2 study to prospectively identify ovarian cancer patients likely to respond to rucaparib 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics November 18-21, 2014 Barcelona, Spain
11.
KP Pennington, T Walsh, MI Harrell, etal: 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

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Published In

Journal of Clinical Oncology
Pages: 2583 - 2584
PubMed: 26124483

History

Published online: June 29, 2015
Published in print: August 10, 2015

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Susan M. Domchek [email protected]
Basser Research Center and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
Bella Kaufman
Sheba Medical Center, Tel Hashomer, Israel
Michael Friedlander
Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia

Notes

Corresponding author: Susan M. Domchek, MD, Basser Research Center and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104; e-mail: [email protected].

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Susan M. Domchek, Bella Kaufman, Michael Friedlander
Journal of Clinical Oncology 2015 33:23, 2583-2584

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