medwireNews: Results from the ATLANTIS trial platform indicate that rucaparib could play a role in the maintenance treatment of metastatic urothelial carcinoma (mUC) with a DNA repair deficiency (DRD) that has responded to first-line platinum-based chemotherapy.
The final results of rucaparib cohort of the phase II study did not show a significant improvement in progression-free survival (PFS) or overall survival (OS) with the PARP inhibitor versus placebo, delegates were told at the 2022 ASCO Genitourinary Cancers Symposium in San Francisco, California, USA.
Simon Crabb outlines the final results of the rucaparib arm of the ATLANTIS trial of maintenance therapy in patients with metastatic urothelial cancer, and discusses them in light of the recent JAVELIN Bladder 100 and ATLAS trials (4:47).
Nevertheless, noting that PFS was extended with rucaparib use and that treatment was “tolerable,” presenting author Simon Crabb (University of Southampton, UK) said: “Further investigation of PARP inhibition for urothelial carcinoma is warranted in molecularly selected patients.”
He explained that the trial was designed to recruit 48 patients with mUC who had achieved a complete or partial response or stable disease after 4–8 cycles of platinum-based chemotherapy and who had met the study’s criteria for DRD, defined as at least 10% genome-wide loss of heterozygosity, a somatic alteration in one of 15 DRD genes, or a germline BRCA1 or BRCA2 mutation.
But the trial recruitment was ended after 40 patients were enrolled, due to pandemic conditions and the release of the JAVELIN Bladder 100 study findings, which demonstrated a significant OS improvement with maintenance use of the PD-L1 inhibitor avelumab versus best supportive care in a similar patient population.
Patients in the rucaparib study were identified from a screening population of 248 ATLANTIS patients, of whom 74 had biomarkers for DRD, most commonly loss of heterozygosity (55%), followed by gene alterations (27.5%) or both biomarkers (17.5%).
Crabb said that the characteristics of the 20 patients randomly assigned to receive rucaparib 600 mg twice daily and the 20 patients given placebo were “reasonably balanced” with regard to DRD biomarkers and other features, such as age, primary tumor site, visceral metastases, and first-line platinum regimen. And he noted that 90% of patients in the trial had achieved a complete or partial response to chemotherapy.
The primary endpoint of PFS was a median 35.3 weeks with rucaparib and 15.1 weeks with placebo, giving a nonsignificant hazard ratio (HR) of 0.53, with PFS events reported for 60% of rucaparib-treated patients and 100% of controls.
The corresponding median durations of OS for rucaparib versus placebo were unreached and 72.3 weeks, and the OS curves crossed at around 60 weeks, giving a nonsignificant HR of 1.22. Deaths were reported for 45% and 70% of these arms, respectively.
A partial response was reported for one participant given rucaparib, prompting Crabb to comment that the longer duration of PFS with rucaparib “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.”
The median duration of treatment was longer for the rucaparib than the placebo arm (median 10 vs six cycles) and the safety profile for the PARP inhibitor was “consistent” with previous reports, the presenter said.
The incidence of treatment-related fatigue with rucaparib versus placebo was higher at both any-grade (63.2 vs 30.0%) and grade 3 (5.3 vs 0.0%), as were any-grade rates of nausea (36.8 vs 5.0%), rash (21.0 vs 0.0%), and increased alanine transaminase (57.9 vs 10.0%), but there were no grade 4 or 5 events.
Session discussant Sandy Srinivas (Stanford University, California, USA) noted that the median PFS duration was “almost double” that achieved by the controls and that median OS has not yet been reached, indicating “a hint of activity for [homologous recombination repair] in urothelial cancer.”
Comparing the findings from ATLANTIS to those of JAVELIN Bladder 100, she suggested that a future study might look at a combination of immunotherapy and a PARP inhibitor in this patient population.
Srinivas emphasized that there are “more questions than answers” with regard to the use of PARP inhibitors for the treatment of mUC, with ongoing trials investigating monotherapy or combination therapy within the neoadjuvant, first-line, subsequent-line, and maintenance settings.
Other challenges include whether to screen trial participants for DRD and the optimal choice of DRD biomarkers, including use of somatic or germline biomarkers, or those in blood or tumor tissue, she concluded.
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This independent news story was supported by an educational grant from Pfizer and Merck Healthcare KGaA, Darmstadt, Germany
ASCO Genitourinary Cancers Symposium; San Francisco, California, USA: 17–19 February 2022