Efficacy and safety of rucaparib in previously treated, locally advanced or metastatic urothelial carcinoma from a phase 2, open-label trial (ATLAS)

Abstract

Background: ATLAS evaluated the efficacy and safety of the PARP inhibitor rucaparib in patients with previously treated locally advanced/unresectable or metastatic urothelial carcinoma (UC).

Methods: Patients with UC were enrolled independent of tumor homologous recombination deficiency (HRD) status and received rucaparib 600 mg BID. The primary endpoint was investigator-assessed objective response rate (RECIST v1.1) in the intent-to-treat and HRD-positive (loss of genome-wide heterozygosity ≥10%) populations. Key secondary endpoints were progression-free survival (PFS) and safety. Disease control rate (DCR) was defined post-hoc as the proportion of patients with a confirmed complete or partial response (PR), or stable disease lasting ≥16 weeks.

Results: Of 97 enrolled patients, 20 (20.6%) were HRD-positive, 30 (30.9%) HRD-negative, and 47 (48.5%) HRD-indeterminate. Among 95 evaluable patients, there were no confirmed responses. However, reductions in the sum of target lesions were observed, including 6 (6.3%) patients with unconfirmed PR. DCR was 11.6%; median PFS was 1.8 months (95% CI, 1.6-1.9). No relationship was observed between HRD status and efficacy endpoints. Median treatment duration was 1.8 months (range, 0.1-10.1). Most frequent any-grade treatment-emergent adverse events were asthenia/fatigue (57.7%), nausea (42.3%), and anemia (36.1%). Of 64 patients with data from tumor tissue samples, 10 (15.6%) had a deleterious alteration in a DNA damage repair pathway gene, including four with a deleterious BRCA1 or BRCA2 alteration.

Conclusions: Rucaparib did not show significant activity in unselected patients with advanced UC regardless of HRD status. The safety profile was consistent with that observed in patients with ovarian or prostate cancer.

Trial registration: This trial was registered in ClinicalTrials.gov (NCT03397394). Date of registration: 12 January 2018. This trial was registered in EudraCT (2017-004166-10).

Keywords: Bladder cancer; Genomic biomarkers; PARP inhibitor; Rucaparib; Urothelial carcinoma.

Conflict of interest statement

PG has served in a consulting role for and has received fees from Clovis Oncology, AstraZeneca, Bayer, Bristol-Myers Squibb, Driver, Dyania Health, EMD Serono, Exelixis, Foundation Medicine, Genentech, Genzyme, GlaxoSmithKline, Heron Therapeutics, Immunomedics, Infinity Pharmaceuticals, Janssen, Merck, Mirati Therapeutics, Pfizer, QED Therapeutics, Roche, and Seattle Genetics; his current institution, University of Washington, received research funding from Clovis Oncology related to this study and from Bavarian Nordic, Bristol-Myers Squibb, Debiopharm, GlaxoSmithKline, Immunomedics, Kure It Cancer Research, Merck, Mirati Therapeutics, Pfizer, and QED Therapeutics unrelated to this study; and his former institution, Cleveland Clinic, received research funding from AstraZeneca, Bayer, Genentech, Merck, Mirati Therapeutics, OncoGenex, and Pfizer unrelated to this study; also acknowledges support from Seattle Translational Tumor Research Program at Fred Hutchinson Cancer Research Center. YL has served in a consulting or advisory role for Astellas, AstraZeneca, Bristol-Myers Squibb, Janssen, Merck Sharp & Dohme, Pfizer, Roche, and Seattle Genetics, and has received research funding from Johnson & Johnson, Merck Sharp & Dohme, and Sanofi. RM-B has served in a consulting or advisory role and/or on the speakers bureaus for Asofarma, AstraZeneca, Bayer, Janssen, Merck Sharp & Dohme, and Sanofi Aventis, and has received travel and accommodation expenses from Clovis Oncology, Astellas, Bayer, Janssen, Lilly, Merck Sharp & Dohme, Pharmacyclics, Roche, and Sanofi Aventis. MYT has received research funding as principal investigator of clinical trials from Clovis Oncology and Bristol-Myers Squibb. YZ has served on advisory boards for Amgen, Castle Bioscience, Eisai, Exelixis, Johnson & Johnson, Novartis, Pfizer, and Roche Diagnostics. SF has served on advisory boards for Aventis, Astellas, and Janssen and received travel and accommodation expenses from Aventis and Janssen. NJV has served on advisory boards for Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Fuji, Janssen, Merck, Pfizer, Roche, and Tolero; is on the speakers bureaus for Bayer, Exelixis, and Sanofi Aventis; has stock options in Caris; has provided legal services to Novartis; and serves on the editorial board of Up-To-Date. EG has received honoraria for advisory boards, meetings, and/or lectures from Pfizer, Bristol-Myers Squibb, Ipsen, Roche, Eisai, EUSA Pharma, Merck Sharp & Dohme, Sanofi-Genzyme, Adacap, Novartis, Pierre Fabre, Lexicon and Celgene; has received unrestricted research grants from Pfizer, Astra Zeneca, Molecular Templates/Threshold, Roche, Ipsen, and Lexicon. NA declares no competing interests. AA has served on advisory boards for AstraZeneca, Merck, and Bristol-Myers Squibb, and has received research funding from Clovis Oncology, AstraZeneca, Bayer, Bristol-Myers Squibb, Esanik, Genentech, Ionis, Janssen, Merck, Progenics, and Prometheus. AN has served in a consulting or advisory role for Clovis Oncology, AstraZeneca, Bayer, BioClin Therapeutics, Bristol-Myers Squibb, Incyte, Janssen, Merck, and Roche, and has received research funding from AstraZeneca and Merck. AR-V has served in a consulting or advisory role and/or on the speakers bureaus for Clovis Oncology, Astellas, Bayer, Bristol-Myers Squibb, Janssen, Merck Sharp & Dohme, Pfizer, and Roche; received honoraria from AstraZeneca and Sanofi Aventis; and received research funding from Merck Sharp & Dohme, Pfizer, and Takeda. SG declares no competing interests. DHJ has participated in an unbranded educational speaker program with Pfizer, and received travel and accommodation expenses from EUSA Pharma and Ipsen. SS has served in an advisory role for Clovis Oncology. KW, DT, AS, AL, RLD, and DN are employees of Clovis Oncology and may own stock or have stock options in that company. SC has served in a consulting or advisory role and/or on speakers bureaus for Clovis Oncology, Astellas Pharma, Bayer, BeiGene Janssen, Pfizer, and Sanofi; received honoraria from GlaxoSmithKline and Novartis; and received research funding from Clovis Oncology, Johnson & Johnson, and Sanofi.

Figures

Fig. 1

Trial profile. ECOG PS Eastern Cooperative Oncology Group performance status; HRD homologous recombination deficiency; ITT intent-to-treat; LOH loss of heterozygosity; NGS next-generation sequencing

Fig. 2

Genome-wide LOH in TCGA-BLCA dataset and tumor tissue samples. Each circle represents a tissue sample, and the bars represent the median and interquartile range. Black circles in the ATLAS dataset highlight samples with deleterious alterations in DDR pathway genes BRCA1, BRCA2, PALB2, or RAD51C. DDR DNA damage response; IQR interquartile range; LOH loss of heterozygosity; TCGA-BLCA The Cancer Genome Atlas Urothelial Bladder Carcinoma

Fig. 3

Efficacy outcomes. Investigator-assessed best response in target lesions per RECIST v1.1 in the ITT population (a) and Kaplan-Meier estimates of progression-free survival as assessed by the investigator in the overall ITT population and HRD subgroups (b). Data cutoff: February 20, 2020. The ITT population only includes patients with measurable disease at baseline and one or more postbaseline tumor assessment (n = 69); each bar represents data from a single patient with 0% change from baseline shown as 0.5% for visual clarity; patients with a deleterious mutation in DDR pathway genes CHEK2, ATM, RAD51C, PALB2, and BRCA1 are indicated. HRD homologous recombination deficiency; ITT intent-to-treat; PFS progression-free survival; RECIST v1.1 Response Evaluation Criteria in Solid Tumors version 1.1

Fig. 4

Genetic alterations in select pathways. Oncoprint generated from 64 tumor samples with sequencing data. Percentages shown indicate the deleterious gene alteration frequencies. *Only FGFR1 and FGFR3 alterations were identified; no FGFR2 alterations were observed. †Only one alteration type is presented when multiple alteration types were found within a single gene. ‡Includes truncating rearrangements. DDR DNA damage repair; HRD homologous recombination deficiency; PD progressive disease; PR partial response; NA not applicable; NE not evaluable; SD stable disease