ctDNA Offers Potential Biomarker for PARP Inhibitor Maintenance Therapy in Epithelial Ovarian Cancer

Ovarian cancer

Circulating tumor DNA (ctDNA) may serve as a tool to aid clinician decision making regarding whether to proceed with or discontinue PARP inhibitor maintenance therapy for patients with recurrent epithelial ovarian cancer (EOC), according to a presentation given by Dahye Lee, MD, at the 2024 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer.¹

Findings from a prospective observational study in 27 patients with recurrent epithelial ovarian cancer revealed that ctDNA is a potential biomarker for minimal residual disease (MRD) monitoring.^1,2 The positive predictive value of recurrence with MRD by ctDNA was 100% and the negative predictive value was 96.7%.¹

Additionally, regarding cases of clinical recurrence, 5 patients had ctDNA detected, with 4 having BRCA wild-type disease and 1 patient had disease harboring a BRCA2 mutation. The patient with BRCA2-mutated disease received second-line therapy with niraparib (Zejula), had lymph node recurrence in the retrocaval area, MRD positivity, and NM_000546.5(TP53):c.217_224del was the marker. Two patients had received second-line olaparib (Lynparza) and 1 had pelvic and extrapelvic recurrence in the left pelvic and paracolic area with no MRD positivity and a marker of NM_000546.5(TP53):c.993+1G>A; the second patient had lymph node recurrence in the supraclavicular, internal mammary, and cardiophrenic area with MRD positivity and a marker of NM_000546.5(TP53):c.524G>A.

Finally, the last 2 patients received third-line olaparib and niraparib, respectively, and had MRD positivity with recurrence in the lymph nodes. For the patient who received niraparib, the site of metastasis was the cardiophrenic area and markers were NM_000546.5(TP53):c.659A>G and NM_000546.5(TP53):c.721T>G – New evolve. For the patient who received olaparib, the site of metastasis was external and iliac as well as the inguinal area, and the marker was NM_000546(TP53):c.773A>C.

“Patient[s] who had progression with MRD negativity recurred after the end of treatment with PARP inhibitors and bevacizumab [Avastin],” Lee, of the Department of Obstetrics and Gynecology at Yonsei University College of Medicine in Seoul, South Korea, and study authors wrote in the presentation.

As ctDNA has been shown to be an effective marker of MRD detection and early detection of disease progression and may be a useful tool for the analysis of PARP inhibitor-resistant mechanisms, investigators conducted the prospective study as there is an unmet need in ovarian cancer to determine the optimal duration of PARP inhibitor treatment. Trials such as the phase 3 SOLO-1 study (NCT01844986) examined 2 years of first-line PARP inhibitor maintenance with olaparib, whereas the phase 3 PRIMA study (NCT02655016) evaluated 3 years with niraparib.

Patients in the prospective study received PARP inhibitor maintenance for at least 2 years and surveillance for relapse included radiologic features from computed tomography and CA-125 levels.^1,2 All patient’s plasma cell-free DNA and buffy coat DNA from blood samples underwent deep sequencing for cfDNA (70,000X average depth of coverage) with targeted NGS for TP53, BRCA1, BRCA2, ARID1A, CCNE1, KRAS, MYC, PIK3CA, and PTEN mutations. Then, ctDNA detection "positional indexing” occurred followed by identification of marker, which was informed for those with a result of tumor NGS (n = 20) and uninformed for those without a result of tumor NGS (n = 7). Additionally, the selection of marker from tumor NGS followed occurred prior to targeted NGS for patients with a result of tumor NGS.

Patients (n = 27) enrolled in the study had a median age of 52 years (range, 39-73) at diagnosis and all had high-grade serous disease. In terms of BRCA status, patients had BRCA1-positive (29.6%), BRCA2-positive (37.0%), homologous recombination deficiency-positive (3.7%), or wild-type (29.6%) disease. The initial treatment received at diagnosis was either primary debulking surgery plus postoperative adjuvant chemotherapy (66.7%) or neoadjuvant chemotherapy with interval debulking surgery and postoperative adjuvant chemotherapy (33.3%).

Further, patients received a PARP inhibitor as maintenance in the first line (40.7%) or later (59.3%) with agents including olaparib (55.6%), niraparib 10 (37.0%), or others encompassing rucaparib or talazoparib (7.4%). The median duration of PARP inhibitor treatment was 28 months (range, 22-71), with 37.0% of patients receiving treatment for 2 years or less, 44.5% for between 2 and 3 years, and 18.5% for over 3 years.

However, in their conclusion, investigators noted that further research with a larger cohort of patients and longer-term follow-up was needed.

Editor’s Note: Dr Lee did not cite any disclosures.

References

1. Lee D, Kim Y-N, Won D, Lee J-Y. Monitoring minimal residual disease in ovarian cancer patients undergoing long-term treatment with PARP inhibitors using circulating tumor DNA. Presented at: 2024 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer; March 16-18; San Diego, CA.
2. Lee D, Kim Y-N, Won D, et al. Detection of minimal residual disease using circulating tumor DNA in patients treated with long-term PARP inhibitors maintenance for epithelial ovarian cancer. International Journal of Gynecologic Cancer. 2024;34:A402. doi:10.1136/ijgc-2024-ESGO.787