乌鸦传媒

A combination of the poly-ADP ribose polymerase (PARP) inhibitor olaparib and the chemotherapy temozolomide shows preliminary activity in advanced uterine leiomyosarcoma that has progressed on chemotherapy.

Leiomyosarcoma, a sarcoma of smooth muscle lineage, accounts for approximately 20% of soft tissue sarcomas, and the uterus is the most common site in women. After total abdominal hysterectomy, metastatic relapse occurs in 50-70% of patients. Gemcitabine plus docetaxel and doxorubicin-based regimens used for initial treatment of unresectable or metastatic uterine leiomyosarcoma provide objective response rates in the range of 14-36% and median progression-free survival (PFS) of 4 to 6 months.

Matthew Ingham, MD, of Columbia University Irving Medical Center in New York City, and colleagues conducted a single-arm, open-label, multicenter, phase II study evaluating the use of olaparib and temozolomide in 22 patients with advanced uterine leiomyosarcoma. As the team described in the , patients with disease progression on one or more prior lines of therapy received temozolomide 75 mg/m² orally once daily with olaparib 200 mg orally twice a day both on days 1-7 in 21-day cycles.

In the following interview, Ingham described the promising activity of the combination in this group of patients.

What does the study add to the literature about using olaparib plus temozolomide for advanced uterine leiomyosarcoma?

Ingham: Until this point, there have been no prospective data on PARP inhibitors in uterine leiomyosarcoma. Retrospective profiling studies have shown that uterine leiomyosarcoma may be a good rationale to test PARP inhibitors.

This is the first prospective trial to validate this hypothesis. We found for patients with a BRCA-like phenotype, this approach may be effective. Temozolomide was given at a lower dose in combination than for chemotherapy effects to potentiate the olaparib.

Uterine leiomyosarcoma is a difficult-to-treat, rare cancer with 3,000 to 4,000 cases in the U.S. Approved drugs are minimally efficacious. What's exciting is in this targeted approach, albeit in a small study, olaparib plus temozolomide appears significantly more effective once patients fail chemotherapy. Targeted treatment takes advantage of new biological findings in this disease.

The overall response rate was 27%. Most notable was the duration of response (DOR). Of the 6 of 22 patients who responded, the mean DOR was 1 year, which is a profound response with meaningful benefit. The median PFS was 6.9 months.

What is the significance of your finding that homologous recombination (HR) defects appear enriched in uterine leiomyosarcoma?

Ingham: Recently, several groups have identified DNA repair pathway in uterine leiomyosarcoma, which may represent a novel therapeutic vulnerability. We found half (9 of 18) of tumors were HR-deficient by the RAD51 assay. In an exploratory analysis, median PFS was prolonged for patients with HR-deficient versus HR-proficient tumors (11.2 v 5.4 months) by RAD51.

It appears we can use the RAD51 assay to identify HR-deficient patients who seem to benefit from this combination treatment. We have shown prospectively that HR deficiency does exist and we can offer a treatment that targets that vulnerability.

Why did you choose the combination of olaparib and temozolomide for clinical evaluation?

Ingham: This combination treatment came out of laboratory studies in cell lines and mice. The combination was more effective than each drug by itself in preclinical studies. Other studies with just PARP inhibitors have shown only modest or little activity. Temozolomide helps increase the activity of PARP inhibitors.

How would you characterize the safety profile of the combination?

Ingham: Toxicity was mostly manageable, and the safety profile was what we expected. The good news is that general side effects, including nausea, vomiting, and fatigue, were not common, and were much less than what's seen with standard chemotherapy. Hematologic toxicity was common, with grade 3/4 neutropenia in 75% of patients and thrombocytopenia in 32%, but this was manageable with dose modification. There were no complications, severe infections, or bleeding from low platelets.

What's the next step in this research?

Ingham: A new phase II/III National Cancer Institute-sponsored trial will compare olaparib plus temozolomide with the current standard of care for PFS and overall survival. About 70 uterine leiomyosarcoma patients will be randomized to olaparib plus temozolomide or the current FDA-approved chemotherapies trabectedin or pazopanib after initial chemotherapy failure. Enrollment could take 18 months, but we enrolled the 22 patients for the phase II trial in half the time expected. We hope enrollment in the phase II/III trial will go quickly because of interest in a new therapy.

What's the main take-home message for practicing oncologists?

Ingham: Uterine leiomyosarcoma is a rare, very aggressive disease with existing chemotherapy treatment showing side effects and little clinical benefit. A targeted therapy may be more effective than the current treatments now available. This could be one of the first targeted therapies in uterine leiomyosarcoma to make clinical inroads.

Read the study here and expert commentary about it here.