Related Experiment Video
Updated: Nov 16, 2025
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
A phase I dose-finding, pharmacokinetics and genotyping study of olaparib and lurbinectedin in patients with advanced
Andres Poveda1, Ana Oaknin2, Ignacio Romero3
1Oncogynecologic Department, Initia Oncology, Hospital Quironsalud Valencia, Avda Blasco Ibañez, 14, 46 010, Valencia, Spain. apoveda@initiaoncologia.com.
Abstract:
The poly (ADP-Ribose) polymerase (PARP) inhibitor olaparib has shown antitumor activity in patients with ovarian or breast cancer with or without BRCA1/2 mutations. Lurbinectedin is an ecteinascidin that generates DNA double-strand breaks. We hypothesized that the combination of olaparib and lurbinectedin maximizes the DNA damage increasing the efficacy. A 3 + 3 dose-escalation study examined olaparib tablets with lurbinectedin every 21 days. The purpose of this phase I study is to determine the dose-limiting toxicities (DLTs) of the combination, to investigate the maximum tolerated dose (MTD), the recommended phase II dose (RP2D), efficacy, pharmacokinetics, in addition to genotyping and translational studies. In total, 20 patients with ovarian and endometrial cancers were included. The most common adverse events were asthenia, nausea, vomiting, constipation, abdominal pain, neutropenia, anemia. DLT grade 4 neutropenia was observed in two patients in dose level (DL) 5, DL4 was defined as the MTD, and the RP2D was lurbinectedin 1.5 mg/m2 + olaparib 250 mg twice a day (BID). Mutational analysis revealed a median of 2 mutations/case, 53% of patients with mutations in the homologous recombination (HR) pathway. None of the patients reached a complete or partial response; however, 60% of stable disease was achieved. In conclusion, olaparib in combination with lurbinectedin was well tolerated with a disease control rate of 60%. These results deserve further evaluation of the combination in a phase II trial.
Insights
The combination of olaparib and lurbinectedin showed a 60% disease control rate in ovarian and endometrial cancers. This PARP inhibitor combination was well-tolerated, warranting further phase II trials.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Olaparib, a PARP inhibitor, shows antitumor effects in ovarian and breast cancers.
- Lurbinectedin induces DNA double-strand breaks.
- Combining these agents may enhance DNA damage and improve efficacy.
Purpose of the Study:
- Determine dose-limiting toxicities (DLTs) of olaparib and lurbinectedin combination.
- Establish the maximum tolerated dose (MTD) and recommended phase II dose (RP2D).
- Evaluate efficacy, pharmacokinetics, and conduct translational studies.
Main Methods:
- A 3+3 dose-escalation Phase I study.
- Administered olaparib tablets with lurbinectedin every 21 days.
- Included 20 patients with ovarian and endometrial cancers.
Main Results:
- The MTD was determined at dose level 4; RP2D is lurbinectedin 1.5 mg/m² + olaparib 250 mg BID.
- Grade 4 neutropenia was the dose-limiting toxicity.
- Achieved 60% stable disease; no complete or partial responses.
- 53% of patients had homologous recombination (HR) pathway mutations.
Conclusions:
- Olaparib and lurbinectedin combination is well-tolerated in ovarian and endometrial cancers.
- The combination achieved a 60% disease control rate.
- Further Phase II evaluation of this combination is warranted.
