Posted September 29, 2017
Elizabeth Swisher, M.D., University of Washington;
Scott Kaufmann, M.D., Ph.D., Mayo Clinic

Defects in homologous recombination (HR), which are found in 30%-50% of ovarian cancers, have been observed to sensitize cancer cells to death by Poly(ADP-ribose) polymerase (PARP) inhibitor treatment [1]. Because PARP is an enzyme that participates in a number of DNA repair pathways, including HR, PARP inhibitors modulate several types of DNA repair. Dr. Elizabeth Swisher, of the University of Washington, and Dr. Scott Kaufmann, of the Mayo Clinic, received a Synergistic Translational Leverage Award from the fiscal year 2012 Ovarian Cancer Research Program (OCRP) to perform genomic studies using samples from the Assessment of Rucaparib in Ovarian Cancer: Phase 2 Trial (ARIEL2) study, a phase II clinical trial, to determine the relationship HR status of the tumors and outcome of PARP inhibitor treatment. The researchers hypothesized that the HR pathway must be disrupted and the non-homologous end joining pathway, a highly error-prone form of DNA repair, must remain intact for ovarian cancer to demonstrate sensitivity to platinum and PARP inhibitor therapies, which were the treatments used in the ARIEL2 trial. They proposed that HR deficiencies could serve as a clinical predictor of a patient's response to treatment.

ARIEL2 is an international, intervention-focused phase II clinical trial designed to define efficacy, safety, and diagnostic markers associated with ovarian, fallopian tube, or primary peritoneal cancer patients� responsiveness to treatment with the PARP inhibitor rucaparib. The study was initiated in September 2013 and the final data collection for the primary outcome measures for Part 1 of the study (the portion related to this grant) occurred in April 2017. ARIEL2 enrolled patients carrying either normal or mutant versions of HR genes, including BRCA1, BRCA2, RAD51C, and RAD51D, which are associated with increased risk of ovarian cancer. Loss of heterozygosity (LOH) was used as a marker for HR deficiency and patients were categorized as high- or low-loss of heterozygosity (LOH). Expression of mutant versions of these genes was associated with high LOH (HR deficiency). Through their collaboration, Drs. Swisher and Kaufmann completed the genetic testing which determined the tumor sequence for the commonly mutated HR genes and LOH status of each patient.

With support from the OCRP, Drs. Swisher and Kaufmann were able to identify a number of mutations in genes related to HR that are associated with increased responsiveness to rucaparib. Tumors with BRCA1 or BRCA2 mutations, whether germline or somatic, had the highest response rate. However, tumors that silenced BRCA1 or harbored mutations in other genes leading to high LOH (HR deficiency) were also associated with improved progression-free survival and better overall response to treatment. The primary outcome of the ARIEL2 study was progression-free survival, the length of time during or after treatment that a patient goes without their cancer progressing or worsening. Preliminary analyses from ARIEL2 revealed that rucaparib treatment resulted in longer periods of progression-free survival for patients with a mutant BRCA gene, all of whom exhibited high LOH. Differences in response to treatment were also observed between high and low LOH in patients with normal copies of the BRCA gene [2]. The results from ARIEL2 were promising and led to the Food and Drug Administration (FDA)�s approval of rucaparib for clinical use.

BRCA gene and LOH status could potentially be used to predict which patients should receive PARP inhibitor therapy [3]. Drs. Swisher and Kaufmann continue to analyze additional DNA repair proteins in these same samples. The clinical predictors identified by Drs. Swisher and Kaufmann have been tested in a randomized phase III clinical trial, ARIEL3, which used rucaparib as maintenance therapy in women with recurrent platinum-sensitive ovarian cancer. The collaborative, synergistic work done by OCRP awardees Swisher and Kaufmann will help fill the critical knowledge gap for clinicians striving to predict which patients will respond best to which treatment plans, lowering the risk of patients being treated with therapies destined to fail them.

Publications

¹ Stover EH, Konstantinopoulos PA, Matulonis UA, and Swisher EM. 2016. Biomarkers of response and resistance to DNA repair targeted therapies. Clinical Cancer Research 22(23):5651-5660.

² https://www.healio.com/hematology-oncology/gynecologic-cancer/news/in-the-journals/%7B23d20ad1-b2d8-4873-8e34-e663595f4acf%7D/homologous-recombination-deficiency-analysis-predicts-parp-inhibitor-benefit-for-ovarian-cancer

³ Swisher EM, Lin KK, Oza AM, Scott CL, Giordano H, Sun J, Konecny GE, Coleman RL, Tinker AV, O�Malley DM, Kristeleit RS, Ma L, Bell-McGuinn KM, Brenton JD, Cragun JM, Oaknin A, Ray-Coquard I, Harrell MI, Mann E, Kaufmann SH, Floquet A, Leary A, Harding TC, Goble S, Maloney L, Isaacson J, Allen AR, Rolfe L, Yelensky R, Raponi M, McNeish IA. 2016. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicenter, open-label, phase 2 trial. The Lancet. Oncology. 18(1):75-87.

Links:

Public and Technical Abstracts: Evaluation of DNA Repair Function as a Predictor of Response in a Clinical Trial of PARP Inhibitor Monotherapy for Recurrent Ovarian Carcinoma

Information about ARIEL2

ARIEL2 Clinical Trial

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