Phase 2 Trial (POLA Study) of Lurbinectedin plus Olaparib in Patients with Advanced Solid Tumors: Results of Efficacy, Tolerability, and the Translational Study

Abstract

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.

Trabectedin and Lurbinectedin Modulate the Interplay between Cells in the Tumour Microenvironment—Progresses in Their Use in Combined Cancer Therapy

“…LUR has been evaluated in combination with ICIs (anti-PD-L1 and anti-CTLA-4 [ 152 ]) and in combination with irinotecan [ 153 , 154 ], ATR [ 122 , 155 ] alone or combined with ATM [ 156 ] and PARP [ 157 ] inhibitors, anti-VEGF [ 158 ] combined with cisplatin [ 83 , 159 , 160 ], paclitaxel [ 158 ], gemcitabine [ 161 ], capecitabine [ 162 ], doxorubicin [ 41 , 163 , 164 ], and immunomodulatory biomolecules such as antibody-drug complexes commonly referred to as ADCs (4C9-DM1 that targets c-Kit [ 165 ]).…”

“…LUR has been combined with irinotecan in ovarian cell clear carcinoma cell lines showing synergistic effects [ 154 ] and in a case report showing BRCA-mutated platinum-resistant ovarian cancer patients had exceptional clinical responses [ 153 ]. LUR + olaparib (PARP inhibitor), in a phase I clinical trial for advanced solid tumours, is feasible and exhibited a disease control rate of 72.6% [ 157 ]. LUR + doxorubicin improved safety in a phase III clinical trial of SCLC [ 164 ], and in a phase II clinical trial, a benefit was observed in several types of metastatic and unresectable sarcomas [ 41 ].…”

“…Redirects T-lymphocyte cytotoxicity to AXL-expressing cells Osteosarcoma [150] TRB + L19-mTNF Pro-inflammatory cytokine Fibrosarcoma [133] Physical agents TRB + radiotherapy Lung cancer, colon cancer [138] Advanced soft tissue sarcoma [139] Localized resectable myxoid liposarcoma [140,141] Retroperitoneal leiomyosarcoma [151] TRB + hyperthermia Osteosarcoma, liposarcoma, synovial sarcoma [137] LUR has been evaluated in combination with ICIs (anti-PD-L1 and anti-CTLA-4 [152]) and in combination with irinotecan [153,154], ATR [122,155] alone or combined with ATM [156] and PARP [157] inhibitors, anti-VEGF [158] combined with cisplatin [83,159,160], paclitaxel [158], gemcitabine [161], capecitabine [162], doxorubicin [41,163,164], and immunomodulatory biomolecules such as antibody-drug complexes commonly referred to as ADCs (4C9-DM1 that targets c-Kit [165]).…”

“…Ovarian clear cell carcinoma [154] BRCA-mutated platinum-resistant ovarian cancer patient [153] LUR + olaparib PARP inhibitor Advanced solid tumours [157] LUR + berzosertib ATR inhibitor Small-cell lung cancer [155] Biological agents…”

Trabectedin and lurbinectedin: Mechanisms of action, clinical impact, and future perspectives in uterine and soft tissue sarcoma, ovarian carcinoma, and endometrial carcinoma

“…None of the patients achieved an objective response, but 60% of these obtained disease stabilization. In the subsequent phase II POLA trial, the combination of lurbinectedin 1.5/m 2 on day 1 + olaparib 250 mg BID on days 1–5 3qwk was administered to heavily pretreated patients with high-grade ovarian cancer, endometrial cancer, and triple-negative breast cancer ( 30 ). There was a trend to a better overall response rate in the patients with endometrial cancer than in those with ovarian cancer ( p = 0.057) ( Table 2 ).…”