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Maintenance therapy with rucaparib following platinum-based chemotherapy prolonged progression-free survival compared with placebo in patients with DNA repair–deficient-positive, metastatic urothelial cancer.
Maintenance therapy with rucaparib (Rubraca) following platinum-based chemotherapy prolonged progression-free survival (PFS) compared with placebo in patients with DNA repair–deficient (DRD)-positive, metastatic urothelial cancer, according to findings from a randomized comparison within the phase 2 ATLANTIS trial published in the Journal of Clinical Oncology.
Twelve (60%) and 20 (100%) PFS events occurred in the rucaparib and placebo arms, respectively. At a median follow-up of 94.6 weeks (range, 11.4-148.9) in patients still alive, the median PFS was 35.3 weeks (80% CI, 11.7-35.6) with rucaparib vs 15.1 weeks (80% CI, 11.9-22.6) with placebo (HR, 0.53; 80% CI, 0.30-0.92; one-sided P = .07).
“In this efficacy signal-seeking phase 2 trial, we found that switch maintenance treatment with rucaparib resulted in clinically meaningful improvement in the primary end point of PFS, despite small numbers,” lead study author Simon J. Crabb, PhD, MBBS, of Southampton Experimental Cancer Medicine Centre, and coauthors, wrote in the publication.
Platinum-based chemotherapy is the standard frontline treatment for patients with metastatic urothelial cancer, but disease progression remains an inevitable reality for almost all patients, and responses are difficult to salvage even with second-line therapy.
Although avelumab (Bavencio) maintenance therapy has since become a standard of care following frontline chemotherapy, most patients will not benefit from immunotherapy, leaving an unmet need for molecularly-directed treatment approaches.
As such, investigators conceptualized the ATLANTIS trial, which is an adaptive, multicomparison, clinical trial platform. As part of this effort, investigators are evaluating several, biomarker-selected switch maintenance therapeutic approaches for patients with metastatic urothelial cancer without disease progression after completing 4 to 8 cycles of platinum-based chemotherapy in a series of parallel, randomized, double-blind, phase 2 comparisons.
To be eligible for enrollment within the rucaparib comparison, patients had to be at least 16 years of age and have a diagnosis of stage IV (stage T4b and/or N1-3 and/or M1), histologically confirmed, DRD-positive urothelial cancer ineligible for curative-intent treatment. Patients also had to have an ECOG performance status between 0 and 2 and were required to begin study treatment within 3 to 10 weeks of completing 4 to 8 cycles of first-line platinum-containing chemotherapy. Notably, patients were excluded for cancer progression during, or at completion of, first-line chemotherapy.
Patients were randomly assigned 1:1 to receive 600 mg of maintenance rucaparib twice a day orally, or placebo, until disease progression.
Patients were determined to be DRD positive if any of the following were present: at least 10% genome-wide loss of heterozygosity and/or alteration in a defined DRD associated gene (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, and RAD54L) and/or prior confirmation of a germline alteration in BRCA1 or BRCA2.
The primary end point of the trial was PFS. Statistical analysis targeted a hazard ratio of 0.5, with a 20% one-sided α. PFS, which was investigator assessed by RECIST v1.1 criteria, was compared between trial arms in the intention-to-treat (ITT) population, within a Cox model. Secondary end points included overall survival (OS), confirmed response rates, maximum percentage decrease in measurable disease, safety, and tolerability.
Out of 248 patients, 74 (29.8%) were DRD positive and 40 were randomly assigned.
Within the ITT population, the median age was 70.5 years (range, 53-86); 35 (87.5%) patients had a primary bladder cancer and 18 (45%) had visceral metastases. Twenty-five patients (62.5%) received prior cisplatin-based chemotherapy and 36 (90%) achieved an objective response to first-line chemotherapy.
Additional results demonstrated that 9 (45%) and 14 (70%) patients in the rucaparib and placebo arms, respectively, had died. The median OS was not reached in the rucaparib arm and 72.3 weeks (80% CI, 51.7-85.4) in the placebo arm (HR, 1.22; 80% CI, 0.62-2.38; P = .35).
One confirmed partial response occurred in one patient (5%) treated with rucaparib. No other objective radiologic responses to treatment occurred on study, in either treatment group. The maximal percentage reduction in measurable disease was comparable between treatment arms, with medians of −5.8% (interquartile range [IQR], −21.2-36.3) and −4.9% (IQR, −17.9-37.7) for rucaparib and placebo, respectively.
In the safety population (n = 39), treatment-related adverse effects (TRAEs) were mostly low grade. Patients received a median of 10 cycles of rucaparib and 6 cycles of placebo.
All-grade TRAEs of fatigue (63.2% vs 30.0%; P = .03), nausea (36.8% vs 5.0%; P = .03), rash (21.1% vs 0%; P = .04), and raised alanine aminotransferase (57.9% vs 10%; P = .003) were more common in the rucaparib arm.
Five (26.3%) patients on rucaparib and 1 (5%) on placebo discontinued treatment because of treatment-related toxicity or patient decision. At least 1 dose reduction was required in 7 (36.8%) patients receiving rucaparib and 4 (20%) receiving placebo. No treatment-related deaths occurred.
The additional toxicity linked with treatment was consistent with previous experience for PARP inhibition, and rucaparib specifically, according to the study authors.
“Further development of PARP inhibition in metastatic urothelial cancer is now warranted,” the authors concluded. “This may require combination strategies and will require further scrutiny of patient genomic phenotypes to optimally integrate into the increasingly complex treatment pathway for this disease.”
Crabb SJ, Hussain S, Soulis E, et al. A randomized, double-blind, biomarker-selected, phase II clinical trial of maintenance poly ADP-ribose polymerase inhibition with rucaparib following chemotherapy for metastatic urothelial carcinoma. J Clin Oncol. Published online August 12, 2022. doi:10.1200/JCO.22.00405