Currently Enrolling Trial Examines Innovative Approach in Inflammatory Breast Cancer

Reshma Jagsi, MD, DPhil

Investigators have hypothesized that adding a PARP inhibitor to radiation therapy may be effective in terms of improving locoregional control rates for patients with inflammatory breast cancer, which are currently approximately 80% or less at 5 years,¹ and the open-label, phase 2 study S1706 (NCT03598257) has been initiated to explore this question, according to Reshma Jagsi, MD, DPhil.

“Local regional recurrence is still quite substantial even with the best standard-of-care advanced systemic therapies [such as] complete modified radical mastectomy surgery and complete comprehensive local regional radiation. Using a creative approach of combining radiation treatment with radiosensitizing medication, such as PARP inhibitors, is a promising approach,” Jagsi explained in an interview with OncLive^®. “Using these agents, which (among other things) inhibit single-strand break repair, appears to lead to radiosensitization in tumor cell lines more than epithelial cell lines. Since the latter are the types of cell lines that we would be worried about contributing to normal tissue toxicity, it’s not surprising that Phase I studies have suggested that it is safe to combine PARP inhibitors with radiotherapy, and the next step is to investigate efficacy.”

Prior studies have revealed that combining PARP inhibitors with radiotherapy may enhance the sensitivity of cancer cells to radiation, intensify DNA damage, and trigger cell death.² Jagsi, who is the Lawrence W. Davis Professor and Chair of the Department of Radiation Oncology at Emory University School of Medicine in Atlanta, Georgia, noted that preclinical studies have suggested radiosensitization occurred in all breast cancer cell lines, not only BRCA-deficient cell lines.

“Radiation treatment causes 25-fold more single-strand breaks than double-strand breaks, and we’ve always talked about double-strand breaks as being the lethal event for a cancer cell,” she explained. “But if there are ways that PARP inhibitors are causing these single-strand breaks to accumulate and then for double-strand breaks to occur at replication forks, [and] if tumor cells are more likely to be deficient in DNA repair, we may have an opportunity to leverage a therapeutic ratio.”

Jagsi also highlighted that this occurrence may be because an underlying commonality of DNA repair deficiency exists that encourages cells to become cancerous in the first place. Investigators now are looking toward this combinatorial approach in the S1706 trial, which Jagsi is the principal investigator for, in patients with inflammatory breast cancer.³

RadioPARP and TBCRC 024 Lay the Groundwork

“The phase 1 study TBCRC 024 [NCT01477489] has helped us settle on an approach for combining PARP inhibition with radiation treatment. There was also a French study, [the phase 1 RadioPARP (NCT03109080) trial], that was conducted that suggests there is safety in combining PARP inhibition with radiation treatment. We are well on our way to using this approach to see if we can improve outcomes in perhaps the most challenging situation radiation oncologists encounter [which is treating inflammatory breast cancer].”

Findings from the multi-institutional TBCRC 024 study of veliparib (ABT-888) and concurrent radiotherapy revealed that long-term monitoring of the toxicity of radiosensitizing agents is key.⁴ Patients with primary inflammatory (n = 25) or locally recurrent breast cancer (n = 5) treated with a radiation dose of 50 Gy per 25 fractions to the chest wall and regional lymph nodes plus a 10 Gy boost, experienced a 3-year progression-free survival rate of 50% and a 3-year overall survival (OS) rate of 34%.² Five dose-limiting toxicities (DLTs) occurred including neutropenia (n = 1) and moist desquamation (n = 4), and approximately half of surviving patients demonstrated grade 3 adverse effects (AEs) at 3 years.⁴

Additionally, data from the prospective, dose-escalation RadioPARP study revealed that olaparib (Lynparza) plus radiotherapy was safe in patients with triple-negative breast cancer who had residual disease after neoadjuvant chemotherapy (n = 24). Of patients who received oral olaparib administered in increasing doses from 50- to 100-, 150-, and 200-mg twice daily, no DLTs were observed, and the maximum tolerated dose was not reached.⁵

Patients received olaparib 1 week prior to radiation therapy and concomitantly thereafter. Following breast-conserving surgery, patients received a total dose of 50.⁴ Gy to the whole breast, and those younger than 60 years received a 63-Gy simultaneously integrated boost to the tumor bed. Next, following radical mastectomy or for unresectable tumors, a total dose of 50.0 Gy was delivered to either the chest wall after mastectomy or to the whole breast for unresectable tumors.

At the 2-year follow-up the maximum treatment-related AEs observed were grade 2 breast pain and fibrosis as well as deformity in 1 patient. Additionally, the 3-year OS rate was 83% (95% CI, 70%-100%) and the 3-year event-free survival rate was 65% (95% CI, 48%-88%).⁵

S1706 Open for Enrollment

S1706 plans to enroll patients at over 200 centers; approximately 48% accrual has been reached thus far.^3,6 Patients will be randomly assigned to receive either standard radiation therapy alone or with olaparib. Olaparib will be given orally twice daily the day before radiation therapy begins until the last day of radiation therapy. Standard radiation includes therapy given 5 days a week for 6 weeks to the chest wall and regional lymph nodes until disease progression or unacceptable toxicity.³

“It’s an innovative approach that is really needed for this aggressive type of breast cancer. Patients with inflammatory breast cancer already should get everything in our arsenal: they start with neoadjuvant systemic therapy—meaning they get up-front chemotherapy and targeted therapy if appropriate and they’ll get endocrine therapy too depending on subtype of disease—and they all should get a modified radical mastectomy and then comprehensive chest wall and regional nodal irradiation. And yet the rates of control even with that best standard of care approach are unacceptable,” Jagsi said. “We want to intensify treatment and therefore this trial is comparing standard radiotherapy to the chest wall and regional lymph nodes alone vs radiotherapy together with a potentially radiosensitizing oral PARP inhibitor olaparib at a very low dose.”

The primary end point is invasive disease-free survival and the secondary end points encompass locoregional recurrence-free interval, distant relapse-free survival, and OS. All end points will be examined for up to 8 years and investigators will also be collecting tissue as well as blood samples throughout the study in anticipation of future inflammatory breast cancer correlative studies.

“This is such an important trial that is underway, and we need every patient who is eligible to be aware of this trial—the tremendous contribution that it can make to our understanding of this difficult disease cannot be overstated,” Jagsi said, noting that the trial will most likely be open until midway through 2025.

Patients with inflammatory breast cancer who are 18 years of age and older with a Zubrod performance status of 0 to 2 are eligible for enrollment. All patients must have adequate renal function, completed neoadjuvant chemotherapy prior to mastectomy, and undergone modified radical mastectomy with pathologic nodal evaluation 3 to 12 weeks prior to random assignment unless they received additional chemotherapy after mastectomy.³

Counts must be at least 1000 mm3 for absolute neutrophils, 100,000 mm³ for platelets, and 9.0 g/dL for hemoglobin within 28 days prior to registration.

Patients cannot have distant metastases, myelodysplastic syndrome/acute myeloid leukemia, gross residual tumor or positive microscopic margins after mastectomy, a history of radiation therapy to the ipsilateral chest wall and/or regional nodes, and unresolved or unstable grade 2 or greater toxicities. They also are not allowed to receive strong or moderate CYP3A inhibitors or inducers during olaparib therapy and cannot have had a previous allogenic bone marrow transplant or double umbilical cord blood transplantation.

“Inflammatory breast cancer is a diagnosis that when I was training struck fear in my heart when I saw the statistics, but since then, outcomes have certainly been transformed by advances in the field,” Jagsi said. “Yet, unlike most forms of curable breast cancer, inflammatory breast cancer still has suboptimal outcomes, with rates of local regional recurrence that are substantially worse than the other forms of the disease that we encounter more frequently. Our understanding of this disease is still behind our understanding in other areas, we don’t even have a clear consistent definition. We need to make advances in this area.”

References

1. Michmerhuizen AR, Pesch AM, Moubadder L, et al. PARP1 inhibition radiosensitizes models of inflammatory breast cancer to ionizing radiation. Mol Cancer Ther. 2019;18(11):2063-2073. doi:10.1158/1535-7163
2. Sun C, Chu A, Song R, et al. PARP inhibitors combined with radiotherapy: are we ready? Front Pharmacol. 2023;14:1234973. doi:10.3389/fphar.2023.1234973
3. Radiation therapy with or without olaparib in treating patients with inflammatory breast cancer. ClinicalTrials.gov. Updated February 16, 2024. Accessed February 16, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT03598257#contacts
4. Jagsi R, Griffith KA, Bellon JR, et al; Translational Breast Cancer Research Consortium. Concurrent veliparib with chest wall and nodal radiotherapy in patients with inflammatory or locoregionally recurrent breast cancer: the TBCRC 024 phase I multicenter study. J Clin Oncol. 2018;36(13):1317-1322. doi:10.1200/JCO.2017.77.2665
5. Loap P, Loirat D, Berger F, et al. Concurrent olaparib and radiotherapy in patients with triple-negative breast cancer: the phase 1 olaparib and radiation therapy for triple-negative breast cancer trial. JAMA Oncol. 2022;8(12):1802-1808. doi:10.1001/jamaoncol.2022.5074
6. A phase II randomized trial of olaparib (NSC-747856) administered concurrently with radiotherapy versus radiotherapy alone for inflammatory breast cancer. SWOG. Accessed February 16, 2024. https://www.swog.org/clinical-trials/s1706