The Emerging Role of PARP Inhibitors in the Treatment of Epithelial Ovarian Cancer

Poly(ADP-ribose) polymerase-1 (PARP-1) is an important novel target in cancer therapy. This enzyme is essential in the repair of single-stranded breaks in DNA via the base excision repair pathway. Drugs which inhibit PARP are emerging as a promising new class of anticancer agents particularly effective against tumors which have lost homologous recombination (HR) through loss of functional BRCA1 and BRCA2. PARP inhibitors potentially represent a major breakthrough for patients with hereditary BRCA-associated cancers. Furthermore their role in sporadic epithelial ovarian cancer is emerging with identification of additional subpopulations of women who may benefit a priority. This paper will summarize the mechanism of action of PARP inhibition and its role in the treatment of BRCA1- and 2-associated cancers. We will then expand on the broader relevance and future directions for PARP inhibition in the clinical setting

Phase II activity trial of high-dose radiation and chemosensitization in patients with macrometastatic lymph node spread after sentinel node biopsy in vulvar cancer: GROningen INternational Study on Sentinel nodes in Vulvar cancer III (GROINSS-V III/NRG-GY024)

Background Standard treatment of early-stage vulvar cancer is a radical, wide, local excision of the primary tumor and a sentinel lymph node (SLN) procedure for the groins. An inguinofemoral lymphadenectomy is no longer necessary for patients who have a negative SLN or micrometastasis (≤2 mm). When there is macrometastasis (>2 mm) in the SLN, an inguinofemoral lymphadenectomy is indicated; however, this procedure is associated with major morbidity, such as wound healing, lymphoceles, and lymphedema. Primary Objective To investigate the safety of replacing inguinofemoral lymphadenectomy by chemoradiation in patients with early-stage vulvar cancer with a macrometastasis (>2 mm) and/or extracapsular extension in the sentinel node. Study Hypothesis Combination of 56 Gy of radiation to the inguinal site and concurrent cisplatin chemotherapy without completion inguinofemoral lymphadenectomy will be feasible and safe, with low groin recurrence rates. Trial Design This is a single-arm, prospective phase II treatment trial with stopping rules for unacceptable groin recurrences. Eligible patients will receive 56 Gy of radiation to the involved inguinal site and chemotherapy with concurrent cisplatin. Major Inclusion/Exclusion Criteria Eligible patients undergoing sentinel node procedure will have stage I, unifocal, invasive (>1 mm depth of invasion) squamous cell carcinoma of the vulva with tumor size 2 mm in the sentinel node and/or extracapsular extension, or more than one sentinel node with micrometastasis ≤2 mm. Primary Endpoint Groin recurrence rate in the first 2 years after primary treatment. Sample Size 157 patients with macrometastases in their SLN. Estimated Dates for Completing Accrual and Presenting Results January 1, 2029. Trial Registration Number NCT05076942

Retroperitoneal Extraovarian Fibrothecoma Mimicking a Malignant Epithelial Ovarian Carcinoma

Background. Fibrothecomas are benign sex cord-stromal tumors which rarely originate outside of the ovary. To date, two such cases have been reported in the literature. We report the third case of an extraovarian fibrothecoma and the first presenting similarly to a metastatic epithelial ovarian cancer. Clinical History. We describe a 62-year-old woman with history, physical examination, and imaging suggestive of metastatic ovarian cancer. CA-125 was elevated at 1291 U/mL. Paracenteses were negative for malignant cells and core biopsy showed spindle cell proliferation. A primary debulking surgery for a presumed ovarian cancer was planned. Method and Results. At surgery, 6 liters of ascites were drained. The uterus, ovaries, peritoneum, and omentum were normal. An 18×11×7 cm retroperitoneal mass was found between the left ureter and the sigmoid mesocolon, wrapped with sigmoid colon. Fallopian tubes and ovaries were normal. The mass was resected en bloc with the sigmoid colon, uterus, ovaries, and omentum. Microscopically, there was spindle cell proliferation typical of fibrothecoma. No ovarian tissue was identified in association with the tumor. Conclusion. This third case of extraovarian fibrothecoma highlights the importance of obtaining histologic evidence of malignancy prior to initiating neoadjuvant chemotherapy for a presumed ovarian cancer.Peer Reviewe

A Pan-Canadian Consensus Statement on First-Line PARP Inhibitor Maintenance for Advanced, High-Grade Serous and Endometrioid Tubal, Ovarian, and Primary Peritoneal Cancers

The majority of patients with advanced, high-grade epithelial-tubo ovarian cancer (EOC) respond well to initial treatment with platinum-based chemotherapy; however, up to 80% of patients will experience a recurrence. Poly(ADP-ribose) Polymerase (PARP) inhibitors have been established as a standard of care maintenance therapy to prolong remission and prevent relapse following a response to first-line platinum-chemotherapy. Olaparib and niraparib are the PARP inhibitors currently approved for use in the first-line maintenance setting in Canada. Selection of maintenance therapy requires consideration of patient and tumour factors, presence of germline and somatic mutations, expected drug toxicity profile, and treatment access. This paper discusses the current clinical evidence for first-line PARP inhibitor maintenance therapy in patients with advanced, high-grade EOC and presents consensus statements and a treatment algorithm to aid Canadian oncologists on the selection and use of PARP inhibitors within the Canadian EOC treatment landscape

Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer.

BACKGROUND: Standard first-line chemotherapy for endometrial cancer is paclitaxel plus carboplatin. The benefit of adding pembrolizumab to chemotherapy remains unclear. METHODS: In this double-blind, placebo-controlled, randomized, phase 3 trial, we assigned 816 patients with measurable disease (stage III or IVA) or stage IVB or recurrent endometrial cancer in a 1:1 ratio to receive pembrolizumab or placebo along with combination therapy with paclitaxel plus carboplatin. The administration of pembrolizumab or placebo was planned in 6 cycles every 3 weeks, followed by up to 14 maintenance cycles every 6 weeks. The patients were stratified into two cohorts according to whether they had mismatch repair-deficient (dMMR) or mismatch repair-proficient (pMMR) disease. Previous adjuvant chemotherapy was permitted if the treatment-free interval was at least 12 months. The primary outcome was progression-free survival in the two cohorts. Interim analyses were scheduled to be triggered after the occurrence of at least 84 events of death or progression in the dMMR cohort and at least 196 events in the pMMR cohort. RESULTS: In the 12-month analysis, Kaplan-Meier estimates of progression-free survival in the dMMR cohort were 74% in the pembrolizumab group and 38% in the placebo group (hazard ratio for progression or death, 0.30; 95% confidence interval [CI], 0.19 to 0.48; P CONCLUSIONS: In patients with advanced or recurrent endometrial cancer, the addition of pembrolizumab to standard chemotherapy resulted in significantly longer progression-free survival than with chemotherapy alone. (Funded by the National Cancer Institute and others; NRG-GY018 ClinicalTrials.gov number, NCT03914612.)