ASCO GU 2020: Results from ATLAS, a Phase 2, Open-Label Trial: Rucaparib for Recurrent, Locally Advanced or Metastatic Urothelial Carcinoma

San Francisco, California (UroToday.com) The treatment of recurrent/refractory advanced urothelial cancer (UC) remains a challenge. Recent practice-changing studies have firmly established checkpoint inhibitor (CPI) immunotherapy as an option for patients who have progressed after chemotherapy. Furthermore, there has been increasing emphasis to identify patient subsets that may benefit from targeted therapies, such as poly (ADP-ribose) polymerase (PARP) inhibitors for tumors with evidence of DNA repair deficiency. In the Rapid Abstract Session, Dr. Petros Grivas from Seattle Cancer Care Alliance presented findings from ATLAS: a Phase II, open-label trial of rucaparib for locally recurrent or metastatic UC.

Rucaparib is a PARP inhibitor approved for the treatment of ovarian cancer. Like ovarian cancer, a subset of UC exhibits defective homologous recombination (HR), evidenced by genomic alterations in HR-associated genes. HR deficiency is a known predictive biomarker of PARP inhibitor response and therefore its use in metastatic UC presents an ideal targeted strategy.

atlas trial schema

Patients with advanced UC who had experienced progression after 1-2 prior treatments (including chemotherapy and CPI) were enrolled irrespective of HR deficiency status. Patients were administered rucaparib 600mg orally BID until radiographic disease progression or unacceptable toxicity. Patients were allowed to continue therapy beyond progression if there was evidence of clinical benefit. The primary endpoint of the study was an investigator-assessed objective response in all patients, as well as those with HRD (per the DX1 NGS assay from Foundation Medicine, Cambridge, MA). Secondary endpoints included duration of response, progression-free survival, overall survival and safety.

In total, 97 patients were enrolled of which 20 patients were HRD+, 30 were HRD- and four were indeterminate. Most patients were male (78.4%) and had progressed after prior cisplatin or carboplatin chemotherapy.

Most frequent treatment-emergent adverse events (TEAEs) were fatigue, nausea/vomiting, anemia, decreased appetite, and thrombocytopenia – all of which have been noted as a class effect of PARP inhibitors including rucaparib. Grade 3 or higher TEAEs included anemia (20.6%) and thrombocytopenia (11.3%).

atlas progression free survival

With respect to efficacy, there were no confirmed responses and 27/95 (28.4%) had a best response of stable disease. The clinical benefit rate in the intention-to-treat population was 12.6%. The clinical benefit was 15.8% in HRD+ and 6.9% in HRD- groups. Median progression-free survival was only 1.8 months in the overall cohort, and this did not appear different among HRD+ (1.4 months), HRD- (1.8 months) and HRD-indeterminate (1.8 months) groups.

Of the subset of patients with available tumors that underwent next-generation sequencing, only 6/62 (9.4%) had evidence of deleterious alteration in DNA damage and repair pathway genes thought to be associated with PARP inhibitor activity (such as BRCA1, BRCA2, RAD51C, and PALB2). In addition, there was a high frequency of TP53 alteration (52.4%) and frequent FGF(R) amplifications.

In summarizing, Dr. Grivas noted that the safety of rucaparib in metastatic UC was consistent with that observed in patients in other tumor types. Owing to the lack of responses, the trial was discontinued due to not meeting the protocol-defined continuation criteria for efficacy. He noted that rucaparib monotherapy may not provide meaningful clinical benefit to unselected patients with advanced recurrent UC.

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: Anis Hamid, MBBS, Medical Oncology Research Fellow at Dana-Farber Cancer Institute and Medical Oncologist, PhD candidate, University of Melbourne, Melbourne, Australia, Twitter: @anis_a_hamid at the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California

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