Abstract
Lurbinectedin is an antitumor agent belonging to the natural marine-based tetrahydroisoquinoline family which has shown very promising clinical activity with a favorable safety profile in many types of cancer. Preclinical evidence showed that lurbinectedin inhibits active transcription and binds to GC-rich sequences, leading to irreversible degradation of RNA polymerase II and generation of single- and double-strand DNA breaks and, as a consequence, apoptosis of tumor cells. In addition, lurbinectedin has demonstrated modulation of the tumor microenvironment and activity against cancer cells harboring homologous recombination DNA repair deficiency. Although considerable improvements have been made in the treatment of epithelial ovarian cancer, most patients with advanced disease experience recurrence with a dismal prognosis due to chemotherapy (mainly platinum) resistance. Platinum-resistant/refractory ovarian cancer remains a difficult-to-treat setting of disease, and currently, the exploration of new therapeutic approaches represents a main field of interest. Although the CORAIL phase III study did not meet its primary endpoint, the results suggest that lurbinectedin might be a valid alternative for patients that have exhausted therapeutic options. This article will focus on the clinical evidence, the most recent investigations, and the future perspective regarding the use of lurbinectedin in ovarian cancer.
Highlights
Ovarian cancer (OC) is the eighth most common malignancy in women, with an estimated 313,959 new cases and 207,252 new deaths in 2020 [1]
In a preclinical study by Xie et al conducted on osteosarcoma cell lines, treatment with lurbinectedin was associated with the stimulation of immunogenic cell death (ICD) as demonstrated by multiple cell modifications, such as the translocation of calreticuline (CALR) at the cell surface, the generation of an autocrine and paracrine response mediated by type I interferons, and the release of nuclear high mobility group box 1 (HMGB1), which is involved in tumor antigen recognition
The phase III, randomized, multicenter CORAIL study failed to demonstrate the superiority of this agent in terms of progression-free survival (PFS) when compared with topotecan and pegylated liposomal doxorubicin (PLD) in platinum-resistant OC patients [13]
Summary
Ovarian cancer (OC) is the eighth most common malignancy in women, with an estimated 313,959 new cases and 207,252 new deaths in 2020 [1]. Lurbinectedin, a synthetic alkaloid originally derived from the marine tunicate Ectenaiscidia turbinata, has shown promising activity against platinum-resistant OC in preclinical models; in addition, some studies suggest that it possesses the capability to modulate the tumor microenvironment and to evoke anticancer immunity Based on these lines of evidence and after the completion of a phase I trial assessing its tolerability and efficacy in advanced solid tumors [10], lurbinectedin was evaluated in platinum-resistant and platinum-refractory OC in a two-stage controlled phase II study, where a remarkable antitumor activity with a 23% overall response rate (ORR) (95% CI, 13%–37%) was reported [11]. To explore its potential synergism and to enhance its therapeutic activity, lurbinectedin is currently being evaluated in several trials partnering with other agents such as PARPi [13]
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