PURPOSE: Immunotherapy and chemotherapy combinations have shown activity in endometrial cancer, with greater benefit in mismatch repair (MMR)–deficient (dMMR) than MMR-proficient (pMMR) disease. Adding a poly(ADP-ribose) polymerase inhibitor may improve outcomes, especially in pMMR disease. METHODS: This phase III, global, double-blind, placebo-controlled trial randomly assigned eligible patients with newly diagnosed advanced or recurrent endometrial cancer 1:1:1 to: carboplatin/paclitaxel plus durvalumab placebo followed by placebo maintenance (control arm); carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib placebo (durvalumab arm); or carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib (durvalumab + olaparib arm). The primary end points were progression-free survival (PFS) in the durvalumab arm versus control and the durvalumab + olaparib arm versus control. RESULTS: Seven hundred eighteen patients were randomly assigned. In the intention-to-treat population, statistically significant PFS benefit was observed in the durvalumab (hazard ratio [HR], 0.71 [95% CI, 0.57 to 0.89]; P = .003) and durvalumab + olaparib arms (HR, 0.55 [95% CI, 0.43 to 0.69]; P < .0001) versus control. Prespecified, exploratory subgroup analyses showed PFS benefit in dMMR (HR [durvalumab v control], 0.42 [95% CI, 0.22 to 0.80]; HR [durvalumab + olaparib v control], 0.41 [95% CI, 0.21 to 0.75]) and pMMR subgroups (HR [durvalumab v control], 0.77 [95% CI, 0.60 to 0.97]; HR [durvalumab + olaparib v control] 0.57; [95% CI, 0.44 to 0.73]); and in PD-L1–positive subgroups (HR [durvalumab v control], 0.63 [95% CI, 0.48 to 0.83]; HR [durvalumab + olaparib v control], 0.42 [95% CI, 0.31 to 0.57]). Interim overall survival results (maturity approximately 28%) were supportive of the primary outcomes (durvalumab v control: HR, 0.77 [95% CI, 0.56 to 1.07]; P = .120; durvalumab + olaparib v control: HR, 0.59 [95% CI, 0.42 to 0.83]; P = .003). The safety profiles of the experimental arms were generally consistent with individual agents. CONCLUSION: Carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab with or without olaparib demonstrated a statistically significant and clinically meaningful PFS benefit in patients with advanced or recurrent endometrial cancer.

PURPOSE: ATHENA (ClinicalTrials.gov identifier: NCT03522246 ) was designed to evaluate rucaparib first-line maintenance treatment in a broad patient population, including those without BRCA1 or BRCA2 (BRCA) mutations or other evidence of homologous recombination deficiency (HRD), or high-risk clinical characteristics such as residual disease. We report the results from the ATHENA–MONO comparison of rucaparib versus placebo. METHODS: Patients with stage III-IV high-grade ovarian cancer undergoing surgical cytoreduction (R0/complete resection permitted) and responding to first-line platinum-doublet chemotherapy were randomly assigned 4:1 to oral rucaparib 600 mg twice a day or placebo. Stratification factors were HRD test status, residual disease after chemotherapy, and timing of surgery. The primary end point of investigator-assessed progression-free survival was assessed in a step-down procedure, first in the HRD population (BRCA-mutant or BRCA wild-type/loss of heterozygosity high tumor), and then in the intent-to-treat population. RESULTS: As of March 23, 2022 (data cutoff), 427 and 111 patients were randomly assigned to rucaparib or placebo, respectively (HRD population: 185 v 49). Median progression-free survival (95% CI) was 28.7 months (23.0 to not reached) with rucaparib versus 11.3 months (9.1 to 22.1) with placebo in the HRD population (log-rank P = .0004; hazard ratio [HR], 0.47; 95% CI, 0.31 to 0.72); 20.2 months (15.2 to 24.7) versus 9.2 months (8.3 to 12.2) in the intent-to-treat population (log-rank P < .0001; HR, 0.52; 95% CI, 0.40 to 0.68); and 12.1 months (11.1 to 17.7) versus 9.1 months (4.0 to 12.2) in the HRD-negative population (HR, 0.65; 95% CI, 0.45 to 0.95). The most common grade ≥ 3 treatment-emergent adverse events were anemia (rucaparib, 28.7% v placebo, 0%) and neutropenia (14.6% v 0.9%). CONCLUSION: Rucaparib monotherapy is effective as first-line maintenance, conferring significant benefit versus placebo in patients with advanced ovarian cancer with and without HRD.

PURPOSE: To provide recommendations on the use of poly(ADP-ribose) polymerase inhibitors (PARPis) for management of epithelial ovarian, tubal, or primary peritoneal cancer (EOC). METHODS: Randomized, controlled, and open-labeled trials published from 2011 through 2020 were identified in a literature search. Guideline recommendations were based on the review of the evidence, US Food and Drug Administration approvals, and consensus when evidence was lacking. RESULTS: The systematic review identified 17 eligible trials. RECOMMENDATIONS: The guideline pertains to patients who are PARPi naïve. All patients with newly diagnosed, stage III-IV EOC whose disease is in complete or partial response to first-line, platinum-based chemotherapy with high-grade serous or endometrioid EOC should be offered PARPi maintenance therapy with niraparib. For patients with germline or somatic pathogenic or likely pathogenic variants in BRCA1 (g/s BRCA1) or BRCA2 (g/s BRCA2) genes should be treated with olaparib. The addition of olaparib to bevacizumab may be offered to patients with stage III-IV EOC with g/s BRCA1/2 and/or genomic instability and a partial or complete response to chemotherapy plus bevacizumab combination. Maintenance therapy (second line or more) with single-agent PARPi may be offered for patients with EOC who have not received a PARPi and have responded to platinum-based therapy regardless of BRCA mutation status. Treatment with a PARPi should be offered to patients with recurrent EOC that has not recurred within 6 months of platinum-based therapy, who have not received a PARPi and have a g/s BRCA1/2, or whose tumor demonstrates genomic instability. PARPis are not recommended for use in combination with chemotherapy, other targeted agents, or immune-oncology agents in the recurrent setting outside the context of a clinical trial. Recommendations for managing specific adverse events are presented. Data to support reuse of PARPis in any setting are needed. Additional information is available at www.asco.org/gynecologic-cancer-guidelines .

OBJECTIVE: To assess efficacy of the levonorgestrel-releasing intrauterine device (LNG-IUD) for treatment of complex atypical hyperplasia or low-grade endometrial cancer. METHODS: This retrospective case series included all patients treated with the LNG-IUD for complex atypical hyperplasia or early-grade endometrial cancer from January 2003 to June 2013. Response rates were calculated and the association of response with clinicopathologic factors, including age, body mass index, and uterine size, was determined. RESULTS: Forty-six patients diagnosed with complex atypical hyperplasia or early-grade endometrial cancer were treated with the LNG-IUD. Of 32 evaluable patients at the 6-month time point, 15 had complex atypical hyperplasia (47%), nine had G1 endometrial cancer (28%), and eight had grade 2 endometrial cancer (25%). Overall response rate was 75% (95% CI 57–89) at 6 months; 80% (95% CI 52–96) in complex atypical hyperplasia, 67% (95% CI 30–93) in grade 1 endometrial cancer, and 75% (CI 35–97) in grade 2 endometrial cancer. Of the clinicopathologic features evaluated, there was a trend toward the association of lack of exogenous progesterone effect in the pathology specimen with nonresponse to the IUD (P=.05). Median uterine diameter was 1.3 cm larger in women who did not respond to the IUD (P=.04). CONCLUSION: Levonorgestrel-releasing IUD therapy for the conservative treatment of complex atypical hyperplasia or early-grade endometrial cancer resulted in return to normal histology in a majority of patients.

Immune checkpoint inhibitors are associated with immune-related adverse events (irAEs), including arthritis (arthritis-irAE). Management of arthritis-irAE is challenging because immunomodulatory therapy for arthritis should not impede antitumor immunity. Understanding of the mechanisms of arthritis-irAE is critical to overcome this challenge, but the pathophysiology remains unknown. Here, we comprehensively analyze peripheral blood and/or synovial fluid samples from 20 patients with arthritis-irAE, and unmask a prominent Th1-CD8⁺ T cell axis in both blood and inflamed joints. CX3CR1^hi CD8⁺ T cells in blood and CXCR3^hi CD8⁺ T cells in synovial fluid, the most clonally expanded T cells, significantly share TCR repertoires. The migration of blood CX3CR1^hi CD8⁺ T cells into joints is possibly mediated by CXCL9/10/11/16 expressed by myeloid cells. Furthermore, arthritis after combined CTLA-4 and PD-1 inhibitor therapy preferentially has enhanced Th17 and transient Th1/Th17 cell signatures. Our data provide insights into the mechanisms, predictive biomarkers, and therapeutic targets for arthritis-irAE.