New Study Examines Safety of Olaparib Plus Low-Dose Radiotherapy in SCLC

Patients with small cell lung cancer (SCLC) are being actively recruited to receive treatment with the PARP inhibitor olaparib (Lynparza) and low-dose radiotherapy in a phase 1 clinical trial sponsored by Memorial Sloan Kettering Cancer Center (MSKCC).¹

Rationale for the use of a PARP inhibitor in combination with radiotherapy comes from the use of radiotherapy with immune checkpoint inhibitors. According to research led by Lizzie E. L. Hendrick, MD, PhD, the success of PARP inhibition with radiotherapy or of ICI therapy in combination with radiotherapy will be determined by the ability to select patients who will likely have long-tern survival along with sustained quality of life in the future.²

“Extensive-stage small cell lung cancer represents a challenging diagnosis to treat. Patients receive at least 4-6 cycles of doublet chemotherapy along with immunotherapy and for those with a systemic response, consolidative radiotherapy to the chest provides additional modest benefit. The current standard-of-care outcome with a 13% 2-year survival rate is clearly lacking. Rupesh Kotecha, MD, chief of radiosurgery, and director of CNS metastasis and radiation oncology, Miami Cancer Institute, told Targeted Oncology™, in an interview. PARP inhibitors, such as olaparib, have been shown in pre-clinical studies to have activity against SCLC cell lines and have been tested in a variety of early clinical trials with demonstrated efficacy and are also well-known radiosensitizing agents. Therefore, this study is evaluating the safety of combining PARP inhibition along with consolidative radiotherapy to the chest as well as report on the clinical outcomes for patients treated with this approach.”

The single-group assignment study (NCT03532880) aims to enroll 24 patients with SCLC to receive olaparib orally twice daily for 3 weeks and thoracic radiation once daily 5 days per week starting 1 week after the initiation of olaparib. Olaparib is administered at 50 mg to 300 mg until disease progression or unacceptable toxicity. Following study treatment, patients enrolled are followed up to week 3 of months 3, 6, 9, and 12. Patients will undergo treatment at 1 of multiple MSKCC locations in New Jersey and New York or at Baptist Alliance Miami Cancer Center in Miami, Florida.1

Patients will be assessed for the coprimary end points of maximum-tolerated dose of olaparib/radiotherapy, and the safety of the combination based on the adverse events profile.

The secondary end points of the study include determining the cumulative incidence of locoregional recurrence within the radiation field at 6 months and 1 year, progression-free survival and overall survival at 6 months and 1 years, and assessment of acute and chronic toxicities up to 1 year. As exploratory analyses, the study will also assess exploratory biomarkers and how they correlate with clinical outcomes, SLFN11 and PARP1 protein expression, gene expression by RNA-Seq, and homologous recombination deficiency and mutational burden per MSK-Integrated Mutation Profiling of Actionable Cancer Targets or whole genome sequencing.

To be eligible for the study, patients aged 18 years or older are required to have histologically documented diagnosis of SCLC, documented extensive disease, no disease progression, and ECOG performance status of 0 or 1, adequate organ and marrow function, and a life expectancy of at least 16 weeks. In addition, patients must have completed induction chemotherapy with a minimum of 4 and no more than 6 cycles of a platinum agent and etoposide within 8 weeks of starting the study.

Patient excluded from the study are those with untreated brain metastases, pneumonitis, or other conditions that may interfere with their treatment outcomes. Patient previously treated with radiotherapy to the thorax, a PARP inhibitor, an investigational product within 30 days of the study’s initiation, CYP3A inhibitors, CYP3A inducers, immunotherapy within 19 days of the study’s intimation, or major surgery within 2 weeks are excluded.

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“Small cell lung cancer is definitively an area that requires multi-disciplinary collaboration between medical oncology and radiation oncology. Given the exciting modern era of precision medicine, we are seeing new agents on the market with demonstrated activity against this aggressive cancer. Similarly, advances in radiation oncology have allowed us to target more areas with radiotherapy to improve local disease control rates. Given the natural history and pattern of disease spread, a combined approach with careful patient selection, individualization of therapeutic choices (immunotherapy and chemotherapy) as well as careful timing, sequencing, and dosing of radiotherapy will be needed to further improve patient outcomes, Kotecha said.

_REFERENCE:

_{1. A study of olaparib and low dose radiotherapy for small cell lung cancer. Clinicaltrials.gov Updated March 2, 2022. Accessed March 21, 2022. https://bit.ly/3uf87Ns}

_{2. Hendriks L, Menis J, Ruysscher D, et al. Combination of immunotherapy and radiotherapy—the next magic step in the management of lung cancer? J Thorac Oncol. 2020;15(2):166-169. doi: 10.1016/j.jtho.2019.12.106.}