San Francisco, California (UroToday.com) During the Rapid Abstract Session B: Urothelial Carcinoma; Penile, Urethral, Testicular, and Adrenal Cancers session at the Annual ASCO GU 2020 meeting in San Francisco, CA, Dr. Petros Grivas presented the results from ATLAS, a phase 2, open-label trial, which evaluated the efficacy/safety of the PARP inhibitor rucaparib in patients with previously treated locally advanced/unresectable urothelial cancer or metastatic urothelial cancer (mUC).
Rucaparib is a PARP inhibitor approved in the United States and European Union for use as treatment or maintenance treatment for patients with recurrent ovarian cancer. Dr. Grivas and colleagues hypothesized a subset of urothelial tumors might be susceptible to PARP inhibition.
- A high proportion of urothelial tumors may exhibit Homologous recombination deficiency (HRD) (i.e., have a deleterious alteration in a gene involved in homologous recombination and/or high genomic loss of heterozygosity)
- Rucaparib has also demonstrated benefit in patients with tumors that are homologous recombination proficient
Dr. Grivas then highlighted the trial schema. Patients with measurable disease who had progressed after 1–2 prior regimens (i.e., platinum-based chemotherapy [PBC] and/or immune checkpoint inhibitors [ICI]) were enrolled regardless of tumor HRD status. Prior PARP inhibitor was not allowed. Patients received rucaparib 600 mg PO BID. Baseline tumor tissue or archival tissue ≤6 months without intervening therapy was required; serial circulating tumor DNA samples were collected. The primary endpoint was investigator-assessed objective response rate (RECIST v1.1) in the intent-to-treat and HRD-positive (defined as genomic loss of heterozygosity ≥10%) populations. Key secondary endpoints were progression-free survival (PFS) and safety. Clinical benefit rate (CBR) was defined as a complete or partial response or stable disease (SD) lasting ≥16 weeks.
Dr. Grivas then highlighted the genomic analyses from the ATLAS trial. Tumor samples were received from 76/97 patients (78.4%). Most tissue samples were recently obtained (less than 6 months; 67/76 (88.2%). Median genomic LOH in ATLAS (n=50) was similar to that found in data from TCGA-Bladder Cancer. Median tumor mutational burden score was 6.3 (n=60), and all ATLAS samples with known status were Microsatellite stable (n=59)
Dr. Grivas then highlighted the results from ATLAS. 97 patients were enrolled (median age was 66); most were men (n=76, 78.4%) and had ECOG PS 1 (n=65, 67.0%). 66 patients (68.0%) had both prior PBC and ICI. 20 patients (20.6%) were HRD-positive, 30 (30.9%) were HRD-negative, and 47 (48.5%) had unknown HRD status; 4 patients had a deleterious BRCA1/2 alteration. Median time on treatment was 54 days.
There were no confirmed responses. Of 96 evaluable patients, 27 (28.1%) had the best response of SD; CBR was 12.5%, and the median PFS was 1.8 months. No relationship was observed between HRD status and clinical activity. Treatment was discontinued by 93 patients (95.9%), mainly due to radiologic or clinical progression (73.1%). Most frequent any grade treatment-emergent (any cause) adverse events were asthenia/fatigue (n=56, 57.7%), nausea (n=40, 41.2%), and anemia (n=34, 35.1%).
Deleterious alterations in DDR pathway genes thought to be associated with PARP inhibitor activity (BRCA1, BRCA 2, RAD51C, and PALB2) were relatively infrequent among the patients with sequencing results (6/64 [9.4%]). Most patient samples exhibited alterations in TP53 (33/63 [52.4%]). Frequent FGF/R amplifications were identified. Co-occurrence of FGF and CCND1 amplifications were observed; CDKN2A and CDKN2B deletions were also commonly seen together.
Dr. Grivas then concluded his excellent presentation with a summary that the safety profile of rucaparib in mUC was consistent with that observed in patients with other solid tumors. There were no confirmed RECIST v1.1 responses; 28.4% of patients had the best response of SD, with no difference in efficacy between the HRD-positive and HRD-negative subgroups. The trial was discontinued because the preliminary efficacy results did not meet protocol-defined continuance criteria, suggesting the rucaparib monotherapy may not provide a meaningful clinical benefit to unselected patients with recurrent mUC. Genomic profiling of ATLAS tissue samples provides expanded insight into the molecular characterization of mUC. Median genomic LOH and deleterious gene alterations observed in this dataset were similar to those in the TCGA-bladder cancer dataset.
Presented by: Petros Grivas, MD PhD, Associate Professor, Clinical Director of Genitourinary Cancers Program, University of Washington, Associate Member, Clinical Research Division, Fred Hutchinson Cancer Research Center
Written by: Abhishek Srivastava, MD, Society of Urologic Oncology Fellow, Fox Chase Cancer Center, Fox Chase Cancer Center, Philadelphia, PA Twitter: @shekabhishek at the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California