Olaparib/Temozolomide Shows Encouraging Efficacy, Manageable Safety in Uterine Leiomyosarcoma

In patients with advanced uterine leiomyosarcoma (uLMS) whose tumors harbor a BRCA-like phenotype, the combination of olaparib (Lynparza) with temozolomide (Temodar) could represent a new standard of care, according to Matthew A. Ingham, MD.

Results from a study phase 2 study (NCT03880019) in this patient population showed that the combination induced an overall response rate (ORR) of 27% with a median progression-free survival (PFS) of 6.9 months (95% CI, 5.4–not evaluable [NE]). Ingham noted that the median duration of response (DOR) was an “impressive” 12.0 months (95% CI, 9.5–NE).

“This speaks to the need to develop an assay or some type of biomarker that can help us predict which patients will be most likely to benefit, because the DOR is clinically meaningful,” he said. “The results seem to compare favorably with some of the other treatment options available.”

In an interview with OncLive^®, Ingham, assistant professor of medicine in the Division of Hematology and Oncology at New York Presbyterian Hospital/Columbia University Medical Center, discussed the encouraging data with the combination of olaparib and temozolomide and how further understanding of the biology of uLMS will advance care for these patients.

OncLive^®: What was the rationale for examining the combination of temozolomide and olaparib in advanced uLMS?

Ingham: uLMS is one of the many subtypes of soft tissue sarcoma. The complexity of sarcoma is that it is a disease with more than 50 or 60 different types. LMS comes from smooth muscle and tends to be one of the more common subtypes of sarcoma. In the advanced setting it is still primarily treated with chemotherapy, which unfortunately provides limited benefit to patients at the expense of significant toxicity.

The rationale for this [trial is based on 2 different concepts]. The first is the observation that some of these tumors may have features of a BRCA-like phenotype. This is similar to what we have seen in breast, prostate, and ovarian cancers, where a subset of the patients have tumors that are deficient in either the BRCA gene or related genes in the homologous recombination [HR] pathway, and that can be therapeutically exploited [through] treatment with PARP inhibitors. There are several studies that suggested that uLMS may have a BRCA-like phenotype.

The second avenue that came together around the same time was some preclinical investigations that were done in a laboratory at Columbia looking at PARP inhibitors, such as olaparib, in uLMS cell lines, either by themselves or with other treatments, including chemotherapy. We found that the combination of olaparib with a lower [than usual] dose of chemotherapy seemed to be a very active combination in uLMS models. We want to try to find new treatment [options] that may be less toxic and more effective than chemotherapy.

Can you explain the trial design?

We conducted a single-arm, phase 2 study with 22 patients. We were able to conduct this study in the Experimental Therapeutics Clinical Trials Network, which is a collaboration among several cancer centers that have early phase clinical trials. One of the things that is positive about this study is that despite this being a relatively rare disease, we were able to accrue the study more quickly than expected. It only took about 6 months or so to accrue all the patients.

This was a signal-seeking study where we treated all patients with a combination of olaparib and temozolomide. We adapted the same dose that had recently been [used in a phase 1 study of patients with] small cell lung cancer so we could move directly to a phase 2 [study]. The design called for 22 patients [to receive] the treatment, [which] was given on days 1 through 7 of a 21-day cycle. [Patients received the combination on a 1 week on, 2 weeks off schedule] to help them recover, particularly with respect to hematologic toxicity. The primary end point was the (ORR), and we were also looking at other secondary objectives, including PFS, as well as toxicity.

Another one of the benefits of this study is that we did obtain biopsies from patients both before they began treatment and while they were on treatment. Our hope is that we can use this tissue to develop some assays that may help us define which patients truly have this BRCA-like phenotype and whether that may predict benefit with [the combination], so that we can select the patients who will derive the most benefit.

What were some of the key highlights of this research?

Overall, we were encouraged by the results of the study, [even though] it is certainly preliminary and it is a relatively small phase 2 study. One of the challenges we face in treating uLMS is that most of the treatment options are cytotoxic chemotherapy. [We are] hoping to try to find a more targeted treatment approach that reflects the biology of the cancer itself. When we think about frontline treatment options with chemotherapy, drugs like doxorubicin or gemcitabine/docetaxel are the traditional [agents] we use. They tend to be associated with response rates [of approximately] 15% to 25% and PFS that is relatively short. 

Some of the other drugs that we use after first-line chemotherapy such as trabectedin [Yondelis] and pazopanib [Votrient], unfortunately, tend to be associated with a relatively short PFS of 3 to 4 months. With our study, the ORR for all patients was 27% and the median PFS was 6.9 months. Certainly, [olaparib plus temozolomide] seems to be worth studying further. One of the most impressive things is that of the patients who did respond, DOR was about 12 months. This speaks to the need to develop an assay, or some type of biomarker, that can help us predict which patients will be most likely to benefit, because the DOR is clinically meaningful. The results seem to compare favorably with some of the other treatment options available.

Were there any notable adverse effects (AEs) associated with this regimen?

Historically, there have been some other studies have looked at PARP inhibitors in combination with temozolomide and other chemotherapies. What was different about our study is that when we studied this preclinically in the lab, it was really apparent that we can lower the dose of the temozolomide while trying to increase the dose of the PARP inhibitor, which seemed to be the most effective approach. [It allowed us to] retain the efficacy of the treatment, even when we use low doses of temozolomide. The benefit of that is ameliorated the hematologic toxicity, meaning no low white blood cell count, no low red blood cell count, and no low platelet count.

In our study, the primary toxicity we saw was myelosuppression, but the silver lining was that we did not see complications of that. Neutropenic fevers, low platelets with bleeding, or other sorts of clinical complications of the low blood counts were not seen. [Approximately] 40% to 50% of patients needed a dose reduction of 1 of the drugs, but that did not seem to impact efficacy. Several patients who responded to the treatment needed a dose reduction relatively early in the course [of treatment].

What impact do you foresee this having on this patient population?

Our goal is to understand the biology of this particular type of sarcoma better. We want to try to move away from chemotherapy as best we can to develop new treatment approaches that are more targeted, with the hope that it could allow us also to treat patients with less toxicity. We do think that a subset of these tumors has a BRCA-like phenotype. In other cancers, we have been able to successfully exploit that with PARP inhibitors, which are targeted drugs.

At this point, we are thinking about how to move this forward, and what we can learn from this study to help patients and to best design a subsequent study. The preliminary results from this study, particularly the DOR, and how well some of the patients [who responded] did, suggest it could be potentially a new standard of care for this disease if some of these results are confirmed in a subsequent study. Our hope is to move this to a randomized clinical trial, where we would compare olaparib and temozolomide, this investigational combination, vs another standard-of-care treatment, perhaps trabectedin, in the third line setting.

We're also trying to learn a little bit more from some of the tissue-based assays from the phase 2 study to see if we can incorporate that into a subsequent study to confirm that we have a test or a biomarker that really selects the patients that are most likely to have the benefit. But we are hoping to [evaluate] this combination further in a randomized study. There are some challenges in terms of pulling that off in a rare disease like [uLMS], but we're hopeful that by working through cooperative groups, and by really partnering with other experts in the field— both from medical oncology with sarcoma, but also from gynecologic oncology—that we can successfully do that and hopefully see if this is an option that would help patient care.

What do you hope that your colleagues take away from these findings?

Generally, I want people to share our hope that maybe we have found something about the biology of uLMS that opens up a new approach to treat this disease. Chemotherapy does certainly provide some efficacy to patients, but all doctors who take care of patients know that. They are hoping that we can have some advances in this disease like patients have had in melanoma or lung cancer, where we have made real progress with targeted drugs and immunotherapy. All sarcoma patients want to see those types of advancements as well. So far for uLMS, that has not happened. We are hopeful that we can help to move the field forward, and maybe move us 1 step closer towards having treatment approaches that are more targeted and less toxic.

Reference

1. Ingham M, Allred JB, Gano K, et al. NCI protocol 10250: A phase II study of temozolomide and olaparib for the treatment of advanced uterine leiomyosarcoma. J Clin Oncol. 2021;39(15):11506.