Abstract
Simple SummaryGenomic instability (GI) is a transversal phenomenon in oncology, constituting a hallmark of cancer. In gynecological malignancies, the predictive value of GI has been described and is mainly caused by alterations in the homologous recombination repair (HRR) genes, such as BRCA1/2. The POLA clinical trial constitutes an ideal substrate used to study the correlation between GI and response to combined therapy of lurbinectedin plus olaparib in solid tumors. In this context, we developed an approach based on next-generation sequencing, capable of shedding information about Copy Number Variations (CNV) as a surrogate of GI and genotyping of homologous recombination repair genes. Additionally, some algorithms used to extract GI parameters were tested and benchmarked, selecting the most informative mutational and GI features as potential predictive biomarkers for the drug combination explored in the POLA trial.We hypothesized that the combination of olaparib and lurbinectedin maximizes DNA damage, thus increasing its efficacy. The POLA phase 1 trial established the recommended phase 2 dose of lurbinectedin as being 1.5 mg (day 1) and that of olaparib as being 250 mg/12 h (days 1–5) for a 21-day cycle. In phase 2, we explore the efficacy of the combination in terms of clinical response and its correlation with mutations in the HRR genes and the genomic instability (GI) parameters. Results: A total of 73 patients with high-grade ovarian (n = 46), endometrial (n = 26), and triple-negative breast cancer (n = 1) were treated with lurbinectedin and olaparib. Most patients (62%) received ≥3 lines of prior therapy. The overall response rate (ORR) and disease control rate (DCR) were 9.6% and 72.6%, respectively. The median progression-free survival (PFS) was 4.54 months (95% CI 3.0–5.2). Twelve (16.4%) patients were considered long-term responders (LTR), with a median PFS of 13.3 months. No clinical benefit was observed for cases with HRR gene mutation. In ovarian LTRs, although a direct association with GI and a total loss of heterozygosity (LOH) events was observed, the association did not reach statistical significance (p = 0.055). Globally, the total number of LOHs might be associated with the ORR (p =0.074). The most common grade 3–4 toxicities were anemia and thrombocytopenia, in 6 (8.2%) and 3 (4.1%) patients, respectively. Conclusion: The POLA study provides evidence that the administration of lurbinectedin and olaparib is feasible and tolerable, with a DCR of 72.6%. Different GI parameters showed associations with better responses.
Highlights
The treatment of ovarian cancer has seen increasing improvement over recent years
Considering that genomic instability (GI) caused by homologous recombination repair (HRR) gene mutations has been principally described in the ovarian cancer population, we studied GI patterns according to cancer type (Supplementary Figure S4)
Hematological toxicity is the major concern of this combination, since only lurbinectedin as therapy showed grade 3–4 neutropenia up to 85% when administered at a flat dose [19], though this was lower (57%) when the dose was adjusted to body surface area [23]
Summary
The treatment of ovarian cancer has seen increasing improvement over recent years. Today, the most critical advance has been the use of poly (ADP-Ribose) polymerase inhibitors (PARPis). In 2009, a phase I study on olaparib presented the first clinical evidence of PARPi having an effect in patients with BRCA1/2 mutations, with the benefits being of a magnitude never observed before [1]. The clinical benefit of PARPi is not limited to patients with BRCA1/2 mutations; the entire population of high-grade serous (HGS) ovarian cancer or triple-negative breast cancer has observed its benefits [2]. In patients with the absence of BRCA alterations, the efficacy of PARPi is more pronounced in those with homologous recombinant deficiency (HRD). Several phase II and III trials have demonstrated the efficacy of PARPi in patients with ovarian cancer [3] and have led to the approval of three PARPis—olaparib, niraparib, and rucaparib—as maintenance therapy for platinum-sensitive recurrent ovarian cancer [4–8]
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