Patients having deficiencies in homologous recombination repair (HRR), primarily as a result of BRCA1 and/or BRCA2 mutations, have shown sensitivity to therapy with PARP inhibitors. In addition to the BRCA genes, other genetic or epigenetic alterations are also associated with HRR deficiency, which can lead to loss of heterozygosity (LOH) and potential PARP-inhibitor sensitivity. Rucaparib is a small molecule orally-bioavailable inhibitor that targets the PARP-1, -2, and -3 isoforms of the enzyme. This compound is undergoing further development for the treatment of cancer patients having tumors that display HRR deficiency.
At the 2017 ASCO Annual Meeting, Anne Patsouris, MD, of the Institut de Cancérologie de l'Ouest Paul Papin, presented an update for the status of RUBY (NCT02505048), a single-arm, multi-center, phase II, open-label study that evaluated the use of rucaparib in HER2- metastatic breast cancer patients having high tumor genomic LOH and/or somatic BRCA mutation status (Abstract TPS1117).
HRR Deficiency, High LOH & PARP Inhibitors
When asked about the mutations that could cause HRR deficiency in patients, Patsouris replied, “In addition to BRCA1/2 mutation, alterations of other genes (such as PALB2 or RAD51C) involved in homologous recombination repair pathways have been found to lead to a BRCA-like phenotype that is associated with sensitivity to PARP inhibitors.” When cells have deficiency in the error-free HRR pathway, then they must rely on other, more error-prone methods for double-strand DNA repairs, such as non-homologous end joining.
She further explained the use of LOH as a proxy for HRR deficiency. “High tumor genomic LOH (we used a high LOH cutoff of 18%) can identify tumors with HRR deficiency, including both known BRCA1 methylation and unknown genetic/epigenetic mechanisms and somatic BRCA1/2 mutations. LOH increases across the genome in tumors that have homologous recombination deficiency due to the use of error-prone DNA repair pathways when HR repair is compromised.”
The enzyme PARP performs the vital function of repairing single-strand DNA breaks or “nicks.” If these single strand breaks are not corrected, then, upon DNA replication prior to cellular division, DNA double strand breaks can form. This is especially important in cells that have lost the ability to repair DNA double strand breaks via the nearly error-free process of HRR. The accumulation of double strand DNA breaks ultimately results in the death of those cells having HRR deficiency.
“Rucaparib, a potent oral PARP-1, -2, and -3 inhibitor, has shown activity in a phase I study of patients with breast cancer associated with homologous recombination deficiency,” Patsouris noted. In December 2016, rucaparib received expedited approval for the treatment of germline or somatic mutant BRCA-associated ovarian cancer patients who have had two or more prior chemotherapy regimens.
RUBY Study Description
Participants in the RUBY study were drawn from two different potential pools. “Patients are eligible for the RUBY trial after they have progressed while on the targeted therapy on the SAFIR02 study (NCT02299999),” Patsouris explained. Additionally, those who were ineligible for randomization for the targeted therapy in the SAFIR02 trial were also considered a potential pool of patients for RUBY. “This group of patients included those who were progressing after their first line of chemotherapy.”
This study was open to HER2- metastatic breast cancer patients having a high genomic LOH phenotype (≥ 18% LOH) or somatic mutations to BRCA1 or BRCA2. When asked about the LOH analysis for these patients, Patsouris noted, “Only one sample was analyzed for each patient. We used molecular data from the SAFIR02 trial, an open-label multicenter, phase II, randomized trial, which is evaluating the use of high-throughput genome analysis as a therapeutic decision tool.” Eligible patients received 600 mg rucaparib orally BID continuously in 28-day cycles until disease progression.
The primary endpoint for this study is the clinical benefit rate (CBR), which is defined by complete response, partial response, and stable disease for 16 weeks or more. The objective response rate will be assessed in accordance with a hierarchic protocol if the CBR is significant. Secondary endpoints include progression-free survival, overall survival, safety, and the evaluation of the prognostic and predictive values of high genomic LOH.
The targeted enrollment for this study is 41 patients, employing a Simon two-stage design (19 patients in the first stage and 22 in the second). When asked about this unique trial design, Patsouris replied, “These two stages were not different; we employ a Simon two-stage design in order to: 1) stop and not expose more patients if the treatment has no efficacy on this population; or 2) stop and initiate a phase III study if the treatment shows great efficacy.”
Key inclusion criteria are as follows: women 18 years or older with histologically-confirmed breast cancer; WHO status of 0/1; no HER2 overexpression. Progressive metastatic disease is required with at least one chemotherapy line in a metastatic setting, as well as a measurable target lesion using RECIST v. 1.1 criteria. Molecular analysis is obtained using the Affymetrix array (OncoScan, CytoScan HD, SNP 6.0) data from the SAFIR02 protocol or other programs. High genomic LOH is defined according to the Clovis genomic signature or an inactivating BRCA1 or BRCA2 somatic mutation without known BRCA germline mutation. Prior to inclusion in this study, a 21-day washout period is required from last chemotherapy or targeted therapy administration as well as recovery from all grade 1 or greater residual toxicities (except alopecia).
One prominent exclusion criterion is a known BRCA germline mutation. “There would not have been enough patients to stratify in the study if we had included germline BRCA mutations. Furthermore, the question of the efficacy of PARP inhibitor treatment in the population of patients with BRCA1/2 germline mutations in this setting is being investigated in other studies. The goal of this study is to determine whether tumors with a BRCA-like phenotype respond to an anti-PARP agent,” Patsouris stated.
Patients were also excluded from this study if their life expectancy was less than 3 months, had prior PARP-inhibitor therapy, had toxicities of grade 2 or higher from any previous anti-cancer therapy (except alopecia), and had all target lesions in a previously irradiated area, unless progression is observed in at least one of them prior to this study. Additionally, if hematopoietic and organ functions, as defined as follows, were outside of the listed tolerances, then patients were also excluded: polynuclear neutrophils < 1.5x109/L; platelets < 100x109/L; hemoglobin ≤ 90 g/L; creatinine clearance ≤ 30 mL/min (as measured or calculated using the Cockroft & Gault formula); bilirubin >1.5x the upper limit of normal (ULN); alanine aminotransferase or aspartate aminotransferase >2.5x ULN, or >5x ULN when liver metastases are present.
When asked about the status of this study, Patsouris replied: “The study background, design, and eligibility criteria were presented at the ASCO ‘Trial in Progress’ session. We provided an update on SNP array data screened and patients enrolled to date. We have enrolled 18 patients in our study and enrollment is ongoing; also, 344 SNP array data have been screened. The trial has an inclusion period of 1 year, a post-treatment follow-up period of 24 months, and an overall trial length of 3.5 years. Our goal is to present the results from this study in a future forum.”
Richard Simoneaux is a contributing writer.
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