Olaparib With High-Dose Chemo and ASCT Shows Potential in R/R Lymphomas

Yago L. Nieto, MD, PhD

Treatment with olaparib (Lynparza) plus vorinostat (Zolinza) with the combination of gemcitabine/busulfan/melphalan (Gem/Bu/Mel) elicited promising clinical activity when given with autologous stem cell transplantation (SCT) in heavily pre-treated patients with relapsed/refractory lymphomas.

Findings come from a single-center phase 1 (NCT03259503) study being investigated at MD Anderson Cancer Center in Houston, TX. According to Yago Nieto, MD, PhD, the combination led to high activity among patients treated at the recommended phase 2 dose of olaparib, dose level 4, at 150 mg orally twice daily.

Positive overall response rates with complete responses achieved, and a manageable toxicity profile was reported, including among patients who had previously been exposed to chimeric antigen receptor (CAR) T-cell therapy.

“The regimen is well-tolerated with the expected adverse effect profile of mucositis, self-limited transaminitis, and diarrhea that resolves in a few days,” Nieto, The University of Texas MD Anderson Cancer Center, Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, told Targeted OncologyTM, in an interview. “Among the 15 patients with measurable disease at the time of transplant, the complete remission rate was 100%. All of the patients had a complete response, including the 5 patients who had progression at the time of enrollment, and including all patients who had failed CAR T previously. With a medium follow-up of 18 months, almost 90% of the patients remain free of progression.”

These findings highlight the potential of this combination compared with chemotherapy alone for the treatment of patients with relapsed/refractory lymphomas undergoing SCT.

In the interview, Nieto, MD, PhD, discussed findings from the phase 1 study assessing olaparib and high-dose chemotherapy in patients with relapsed/refractory lymphomas.

ASCT | Image Credit: © Artur - www.stock.adobe.com

Targeted Oncology: What was tested in this phase 1 trial?

Nieto: This is a study where we tested the hypothesis that a PARP inhibitor called olaparib combined with high-dose chemotherapy would be synergistic through inhibition of DNA damage repair. Olaparib is a PARP inhibitor that is FDA-approved for use in certain solid tumors like breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer, but it hasn't been tested in hematological malignancies.

When combined with chemotherapy at lower than conventional doses in ovarian cancer, it showed a potential increase of activity, but the effect was limited by increased myelotoxicity. We thought that the setting of autologous stem cell transplantation would be the perfect setting to test this hypothesis as myeloablation is not only anticipated with use of high-dose chemotherapy, but also can be easily circumvented with the use of stem cell support.

What are the methods and design of the study?

This was a phase 1 trial where we dose-escalated olaparib, and we combined it with our standard regimen of vorinostat combined with Gem/Bu/Mel. This was based on preclinical work in our lab where we saw that the combination of olaparib with these drugs in refractory TMB lymphoma cell lines substantially increased the cytotoxicity, the apoptosis, and it resulted in greater expression of markers of the DNA response pathway, as well as markers of DNA damage accumulation. That preclinical work led to this clinical trial.

Please explain the updated data from this study.

We found that dose level 4 at a dose of 150 mg orally twice a day of olaparib was the maximum tolerated dose, and we expanded the MTD. We have enrolled a total of 35 patients so far. They had been pretreated with a median of 3 prior lines, and about a third of them had failed previous CAR T. Of the 35 patients, 15 had active disease coming into transplant, and 5 of them had progressive disease coming into transplant. The regimen is well-tolerated with the expected adverse effect profile of mucositis, self-limited transaminitis, and diarrhea that resolves in a few days.

Among the 15 patients with measurable disease at the time of transplant, the complete remission rate was 100%. All the patients had a complete response, including the 5 patients who had progression at the time of enrollment, and including all patients who had failed CAR T previously. With a medium follow-up of 18 months, almost 90% of the patients remain free of progression.

What are the implications of these findings?

We are completing the expansion of the MTD. This is a regimen, I believe, [has] very high activity based on the principle of inhibiting DNA damage repair following administration of high-dose chemotherapy that causes massive DNA damage to the tumor cells. This is an important niche in this time and age for patients who fail CAR T, which is close to 60% of those patients receiving CAR T. We have signals of extraordinary activity in this subset of patients.

What unmet needs still exist in this space?

One unmet need is patients who fail CAR T, which is more than half of the patients who receive this treatment. Allogeneic transplant is an option, but it's a fairly toxic option with a treatment-related mortality of around 40%, as shown in a multicenter study we recently published, and a long-term event-free survival rate between 30% and 40%, so not that great either. I think we need a high-dose chemotherapy regimen for those patients who are substantially more active than what we have right now. We have to hit the tumor where it hurts most, which is inhibiting the pathways through which it repairs the damage caused by high-dose chemotherapy.

What should community oncologists know about these data?

I hope this becomes a viable option for patients with refractory lymphomas, which is substantially less toxic than an allogeneic transplant and possibly more active. We are basing this proposal on the novel concept of combining chemotherapy that causes a great degree of DNA damage to the tumor cells, and at the same time, inhibiting with olaparib, the mechanisms through which the tumor cells repair such DNA damage.

We hope that in a subsequent study, we will show our results in a larger population of great activity and good tolerance are confirmed in patients who fail CAR T, and it will become a good option for those patients.

_REFERENCE:

_{Nieto Y, Yang Z, Valdez BC, et al. 38 - Safety and Efficacy of a New High-Dose Chemotherapy Regimen of Panobinostat, Gemcitabine, Busulfan and Melphalan (Pano/GBM) with Autologous Stem Cell Transplant (ASCT) for Patients with High-Risk or Refractory/Relapsed Myeloma – Matched Pair Comparisons with a Concurrent Control Cohort. Presented at: 2023 Transplantation & Cellular Therapy Meetings; February 15-19, 2023; Orlando, FL. Abstract 38.}