Author: By Lynda Williams, Senior medwireNews Reporter
medwireNews: Rucaparib may have potential as a maintenance therapy, despite not showing a significant survival benefit, for patients with metastatic urothelial carcinoma (mUC) and a DNA repair deficiency (DRD) biomarker who have responded to platinum-based chemotherapy, say UK researchers.
Simon Crabb, from the University of Southampton, presented the final results for the phase II study of the PARP inhibitor – part of the ATLANTIS trial platform for mUC – at the 2022 ASCO Genitourinary Cancers Symposium in San Francisco, California, USA.
The session discussant Sandy Srinivas, from Stanford University in California, USA, noted that although the trial did not meet its primary endpoint of a significant progression-free survival (PFS) gain with rucaparib versus placebo, perhaps because of reduced enrolment, there was “definitely an improvement in PFS, which is almost double that of placebo” and “the OS [overall survival] numbers have not yet been reached.”
The study included patients with stage IV UC who achieved stable disease or a better response after four to eight cycles of first-line chemotherapy and who tested positive for DRD, defined as a 10% or greater genome-wide loss of heterozygosity, somatic alterations in BRCA1, BRCA2, ATM or one of 12 other DRD genes, or a known BRCA1 or BRCA2 germline mutation.
Simon Crabb explained that while the initial trial design aimed to recruit 48 patients, recruitment was halted after 40 participants were enrolled, initially because of the SARS-CoV-2 pandemic, and then following study findings in June 2020 from the JAVELIN Bladder 100 trial demonstrating the benefit of maintenance avelumab in the mUC setting.
Of the 248 patients screened for the rucaparib cohort, 74 tested positive for DRD biomarkers and 40 were randomly allocated to receive rucaparib 600 mg twice daily (n=20) or placebo on the basis of loss of heterozygosity (55.0%), DRD gene alterations (27.5%) or both (17.5%).
The presenter described the two trial arms as being “reasonably balanced” with regard to DRD biomarkers and other characteristics, with the majority of patients having primary tumours of the bladder and approximately half having visceral metastases. Thirty percent of patients in each group had achieved a complete response, 60% a partial response and 10% stable disease to their frontline regimen, most commonly cisplatin-based chemotherapy (60–65%).
The primary endpoint of a PFS event was reached by 60% of rucaparib-treated patients and 100% of controls; the median duration of PFS was longer with rucaparib, at 35.3 versus 15.1 weeks, but the hazard ratio of 0.53 did not reach statistical significance.
Similarly, there was a trend towards an improvement in OS with rucaparib versus placebo, with the median unreached versus 72.3 weeks. The OS curves crossed after around 60 weeks of follow-up and the hazard ratio of 1.22 did not reach statistical significance.
Simon Crabb also reported that rucaparib-treated patients had a longer duration of treatment than controls, at a median of 10 versus six 4-week cycles of treatment. One patient given the PARP inhibitor achieved a partial response and three remained on treatment at the time of analysis versus none of the control arm.
“The difference between progression-free survival between the arms of this trial appears to have been primarily because of maintenance of a pre-existing response to prior chemotherapy rather than […] producing new objective responses during maintenance treatment”, he observed.
Treatment-related adverse events were “consistent” with previous reports for rucaparib and “predominantly low grade, with no grade 4 or 5 events”, the presenter continued.
He said that patients given rucaparib were more likely than controls to experience grade 3 (5.3 vs 0.0%) and any-grade fatigue (63.2 vs 30.0%), as well as any-grade nausea (36.8 vs 5.0%), rash (21.1 vs 0.0%) and elevated alanine transaminase (57.9 vs 10.0%).
The presenter summarised that rucaparib treatment was “tolerable” and extended PFS, and he concluded that “further investigation of PARP inhibition is warranted in urothelial carcinoma within a molecularly selected group of patients.”
Noting that avelumab maintenance has the set the standard for first-line mUC with median PFS and OS durations of 3.7 and 21.4 months, respectively, in the JAVELIN Bladder 100 trial, Sandy Srinivas wondered what a trial investigating a combination of immunotherapy and PARP inhibitors might show.
Reference
Crabb SJ, Hussain SA, Soulis E, et al. A randomized, double blind, biomarker selected, phase II clinical trial of maintenance PARP inhibition following chemotherapy for metastatic urothelial carcinoma (mUC): Final analysis of the ATLANTIS rucaparib arm. J Clin Oncol 2022;40:(suppl 6; abstr 436). DOI: 10.1200/JCO.2022.40.6_suppl.436
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