Phase 2 Trial (POLA Study) of Lurbinectedin plus Olaparib in Patients with Advanced Solid Tumors : Results of Efficacy, Tolerability, and the Translational Study
Poveda, Andres (Hospital Quironsalud (Valencia). Oncogynecologic Department)
Lopez-Reig, Raquel (Fundació Institut Valencià d'Oncologia)
Oaknin, Ana (Vall d'Hebron Institut d'Oncologia)
Redondo, Andres (Instituto de Investigación Sanitaria del Hospital Universitario La Paz)
Rubio, Maria Jesus (Hospital Universitario Reina Sofía (Còrdova, Espanya))
Guerra, Eva (Hospital Universitario Ramón y Cajal (Madrid))
Fariñas-Madrid, Lorena (Vall d'Hebron Institut d'Oncologia)
Gallego, Alejandro (Instituto de Investigación Sanitaria del Hospital Universitario La Paz)
Rodriguez-Freixinos, Victor (Vall d'Hebron Institut d'Oncologia)
Fernandez-Serra, Antonio (Fundació Institut Valencià d'Oncologia)
Juan, Óscar (Pivotal SLU (Madrid))
Romero, Ignacio (Fundació Institut Valencià d'Oncologia)
López-Guerrero, J.A (Fundació Institut Valencià d'Oncologia)

Data:	2022
Resum:	Genomic 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.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Estudi clínic ; recerca ; Versió publicada
Matèria:	Ovarian cancer ; Endometrial cancer ; Lurbinectedin ; Olaparib ; Genomic instability
Publicat a:	Cancers, Vol. 14 Núm. 4 (february 2022) , ISSN 2072-6694

DOI: 10.3390/cancers14040915
PMID: 35205662

16 p, 1.6 MB

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