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Treatment with trabectedin monotherapy did not extend median overall survival (OS) in a prospective, open-label randomized phase III study of recurrent ovarian cancer with BRCA-mutated or BRCAness phenotype. Moreover, Domenica Lorusso, MD, PhD, of Fondazione Policlinico Universitario A. Gemelli IRCCS and Catholic University of Sacred Heart in Rome, and colleagues reported, the safety profile was worse than physician's choice of chemotherapy. Outcomes were also not improved in the subgroup of patients who had received previous poly (ADP-ribose) polymerase inhibitor (PARPi) therapy.

It has been known that patients whose disease progresses after front-line platinum-based chemotherapy followed by a PARPi or bevacizumab as maintenance treatment have disappointing outcomes with second- and further-line chemotherapy, and there has been no effective standard chemotherapy regimen.

The phase II suggested that trabectedin as monotherapy could be effective in patients with recurrent ovarian cancer with BRCA mutation and/or BRCAness phenotype. ("BRCAness" describes the phenotypic traits that some sporadic ovarian tumors share with tumors in BRCA1/2 germline mutation carriers and reflects similar causative molecular abnormalities, Lorusso and co-authors explained.

Their prospective, open-label, randomized phase III MITO-23 trial, published in the , evaluated the activity and safety of trabectedin at 1.3 mg/m² given once every 3 weeks (arm A) in patients with BRCA 1/2 mutations or BRCAness phenotype who responded to two or more previous platinum-based treatments. Patients had recurrent ovarian cancer, primary peritoneal carcinoma, or fallopian tube cancer. The treatment was compared with physician's choice of chemotherapy in the control arm B, which included pegylated liposomal doxorubicin, topotecan, gemcitabine, once-weekly paclitaxel, or carboplatin.

The following Q&A discusses the details of the study. The authors were not available for comment, and the answers are from the text of the report.

What are the highlights of the study?

A total of 244 patients from 21 centers were randomly assigned -- 122 in each arm. More than 70% of patients had received three or more previous lines of chemotherapy and 35.7% had received a PARP inhibitor before enrollment.

Median OS (the primary endpoint) was not significantly different between the arms: 15.8 months in arm A versus 17.9 months in arm B. Median progression-free survival (PFS) was 4.9 months in arm A versus 4.4 months in arm B. Among 208 patients evaluable for efficacy, the objective response rate was 17.1% in arm A and 21.4% in arm B, with comparable median duration of response -- 5.6 months in each arm.

No superior effect was observed for trabectedin in the prespecified subgroup analyses according to BRCA mutational status, chemotherapy type, and pretreatment with a PARPi and/or platinum-free interval.

How did the safety profile compare between the two arms?

Trabectedin showed a higher frequency of grade 3 or higher adverse events, serious adverse events (SAEs), and serious adverse drug reactions compared with control chemotherapy. Overall, 82% and 78.6% of all adverse events were considered to be treatment-related in arm A and arm B, respectively. Eighty-six patients (71.1%) and 59 (50%) in arms A and arm B, respectively, had at least one grade 3 or higher adverse event.

The most common grade 3 or higher adverse events reported in arm A were neutropenia (34.7%), fatigue (15.7%), and hepatic toxicity (14.9%), while in arm B, these were neutropenia (12.7%), thrombocytopenia (8.5%), and fatigue (6.8%).

Of 100 SAEs, 86 occurred in 30 patients (24.8%) in arm A and 14 in seven patients (5.9%) in arm B. The most frequent SAEs in arm A were intestinal obstruction (10.5%), fatigue, febrile neutropenia, and nausea (4.7% each), while in arm B, it was intestinal obstruction (13.3%).

Sixteen patients presented with at least one of 36 treatment-emergent serious adverse drug reactions of any grade -- 30 in arm A and six in arm B.

The safety profile of trabectedin observed in this study was similar to that reported in previous studies with no new safety signals.

How could a possible cross-resistance to platinum have affected the results?

The MITO-23 trial included more than 35% of patients who were already pretreated with a PARP inhibitor. The mechanism of action of PARP inhibitors is largely complementary to that of platinum salts, and the existence of possible cross-resistance with platinum that could lead to resistance to subsequent platinum-based chemotherapies has been hypothesized.

The results of the exploratory OS and PFS analysis in 87 patients pretreated with a PARP inhibitor showed no difference between trabectedin and control chemotherapy.

What is the main message for practicing oncologists?

Trabectedin did not meet the primary end point of an OS benefit in comparison with physician's choice chemotherapy in patients with BRCA-mutated or BRCAness recurrent ovarian cancer. Ongoing translational analyses (including homologous recombination deficiency and homologous recombination repair evaluation, microRNA expression, and tumor microenvironment immunologic composition) will possibly help in identifying predictive biomarkers of response/resistance to trabectedin and the patients who may gain long-term benefit from the treatment.

Read the study here.