small molecules

2026-09-15 | Rethinking Menopausal Hormone Therapy After Risk-Reducing Salpingo-Oophorectomy in Women at High Risk for Breast Cancer.

Women who inherit a germline mutation in a hereditary breast and ovarian cancer syndrome gene are recommended to have their fallopian tubes and ovaries removed 5-15 years before the age of natural menopause to prevent the development of ovarian or fallopian tube cancer. Early surgical menopause can lead to several acute and chronic health implications, and, although menopausal hormone therapy (MHT) remains the most effective way to mitigate these issues, use remains suboptimal. This is particularly discernible in populations who face extremely high lifetime risks of developing breast cancer, likely related to the misinformation surrounding its use on subsequent breast cancer risk. Here, we provide a summary of the literature on MHT use and breast cancer as it pertains to high-risk populations, notably BRCA1 and BRCA2 mutation carriers. We also introduce our intention to evaluate how newer formulations such as conjugated estrogen combined with the selective estrogen receptor modulator bazedoxifene may treat symptoms, maintain bone health, and potentially decrease breast cancer risk. Results would be transformative for menopause management in women with hereditary breast and ovarian cancer syndrome and inform guidelines on the safety of MHT in this unique population.

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2026-08-27 | Relacorilant in Combination With Nab-Paclitaxel for the Treatment of Adults With Platinum-Resistant Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

OBJECTIVE: To review the pharmacology, efficacy, and safety of relacorilant (Lifyorli) in combination with nab-paclitaxel (NP) for the treatment of adults with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received 1 to 3 prior lines of systemic therapy, including at least one bevacizumab-containing regimen. DATA SOURCES: A literature search was conducted using Embase and PubMed/MEDLINE, applicable published abstracts, and ongoing studies from ClinicalTrials.gov between January 1, 1981, and July 1, 2026. Keywords included relacorilant, Lifyorli, and CORT125134. STUDY SELECTION AND DATA EXTRACTION: All English-language studies involving relacorilant for the treatment of cancer or other conditions were included. DATA SYNTHESIS: Relacorilant is a highly selective, nonsteroidal, reversible glucocorticoid receptor antagonist approved in combination with NP based primarily on a phase 3 clinical trial of 381 patients, in which relacorilant plus NP significantly improved progression-free and overall survival compared with NP alone. Serious adverse events (AEs) occurred in 35% of patients receiving the combination, although treatment discontinuation due to AEs was uncommon. Common AEs associated with the combination included neutropenia, anemia, thrombocytopenia, nausea, and fatigue.Relevance to Patient Care and Clinical Practice in Comparison With Existing Drugs:Platinum-resistant ovarian cancer remains a difficult-to-treat disease with limited therapeutic options. Unlike biomarker-restricted therapies, relacorilant plus NP improved survival outcomes in a heavily pretreated, biomarker-independent population. CONCLUSION: Relacorilant represents a novel strategy for reversing chemoresistance in combination with NP alongside a manageable safety profile for heavily pretreated patients with platinum-resistant epithelial ovarian, fallopian tube, and primary peritoneal cancers.

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2026-08-19 | Cost-Effectiveness of Opportunistic Salpingectomy During Various Nongynecological Abdominal Surgeries for the Prevention of Tubo-Ovarian Carcinoma: Results From a Markov Modeling Study.

Opportunistic salpingectomy (OS), the additional removal of the fallopian tubes during abdominal surgery, is a preventive strategy against tubo-ovarian carcinoma. Little is known about the economic impact of OS during nongynecological surgeries. Markov state transition models were created comparing the addition of OS in women aged 35 to 65 during cholecystectomy, bariatric surgery, nephrectomy for renal cell carcinoma, and colectomy for colorectal cancer to no addition of OS. Quality-adjusted life-years (QALYs) and healthcare costs were modeled over a lifetime horizon, and uncertainty was assessed with sensitivity analyses. A willingness-to-pay threshold of €20 000 was applied. OS during cholecystectomy and bariatric surgery resulted in a QALY gain of 0.033 and 0.034, and a cost reduction of €12 and €7 per patient, respectively. The probability that OS is cost-effective exceeded 99%. OS during nephrectomy for renal cell carcinoma or colectomy for colorectal cancer yielded a QALY gain of 0.012 and 0.016 and a cost increase of €39 and €25 per patient, respectively. The probability that OS is cost-effective was 94.2% and 96.6%. Modeling OS during nongynecological surgeries for benign indications suggests that the procedure may be cost-effective, resulting in QALY gain and potential cost savings. For oncologic indications OS appears to be cost-effective, yielding a gain in QALYs, while also leading to an increase in costs. However, the results should be considered exploratory and interpreted with caution in light of the model assumptions.

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2026-06-27 | Evaluating homologous recombination status and the efficacy/safety of PARP inhibitors in advanced epithelial ovarianl cancer: A single-institute preliminary experience.

Evaluating homologous recombination (HR) status is essential for determining the efficacy of PARP inhibitors (PARPi) in advanced epithelial ovarian, tubal, and peritoneal cancers. However, data from Taiwan remains limited. This study reports preliminary findings on HR status evaluation and PARPi treatment outcomes. We conducted a retrospective analysis of patients diagnosed with advanced epithelial ovarian, tubal, and peritoneal cancer at a single institute between January 2021 and January 2024. HR status was assessed using ACT or Sofiva Genomics under the CareHRD Project in Taiwan. The safety and efficacy of PARPi were evaluated, and Kaplan-Meier and Cox regression analyses identified factors associated with progression-free survival (PFS). Among 128 patients, 30 (23.4%) were BRCAm, 28 (21.9%) were HRd/BRCAwt, 31 (24.2%) were HRp, and 39 (30.5%) had unknown HR/BRCAwt status. A total of 43 patients received PARPi (29 BRCAm, 12 HRd/BRCAwt, 1 HRp, 1 unknown HR/BRCAwt). Full-dose PARPi was initiated in 32 patients (74.4%), with 22 (51.2%) requiring dose adjustments. At a median follow-up of 25.5 months, PARPi maintenance significantly improved PFS, with median PFS not reached versus 12.2 months in non-users (HR 0.332, 95% CI 0.184-0.589). Three-year PFS was 57.2% vs 22.2%. In the HRd-positive subgroup, PARPi use also prolonged PFS (p= 0.006), with multivariate analysis confirming a 74% reduction in progression risk (HR 0.256, 95% CI 0.085-0.771). The HRd rate in this Taiwanese cohort aligns with existing literature. PARPi significantly improved survival in HRd patients, but adverse events necessitate careful hematological monitoring for treatment sustainability.

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2026-06-20 | Occult invasive and preneoplastic lesions at risk-reducing salpingo-oophorectomy in BRCA1/2 carriers: A multicenter retrospective cohort study.

To evaluate the prevalence and spectrum of occult invasive or preneoplastic lesions detected at risk-reducing salpingo-oophorectomy (RRSO) in BRCA1/2 carriers and to describe recurrent BRCA variants in a regional multicenter cohort. This multicenter retrospective cohort study included 291 women with documented germline pathogenic BRCA1/2 alterations who underwent RRSO at three referral centers in Apulia, Italy, between 2020 and 2025. The primary endpoint was occult invasive or microinvasive tubo-ovarian malignancy at final histopathology. Secondary endpoints included serous tubal intraepithelial carcinoma (STIC), the distribution of histopathologic findings, distribution according to BRCA group, and recurrent annotated BRCA variants. After excluding one patient with ovarian metastasis, occult invasive or microinvasive tubo-ovarian malignancy was identified in 24/290 patients (8.3%), while STICs were identified in 5/290 (1.7%). STIL was observed in 3/291 patients (1.0%). Overall, 29/290 patients (10.0%; 95% confidence interval 7.1-14.0) met the composite endpoint of occult invasive or microinvasive primary tubo-ovarian malignancy or STIC. Among pathogenic variant carriers, the prevalence of the same endpoint was 20/159 (12.6%) in BRCA1 carriers and 9/131 (6.9%) in BRCA2 carriers (p = 0.119). Specific BRCA mutation was available for 154/291 patients (52.9%); BRCA1 c.5266dupC was the most frequent recurrent annotated variant, accounting for 43/154 (27.9%) annotated variants overall and 43/81 (53.1%) annotated BRCA1 variants. In this multicenter BRCA1/2 cohort, occult invasive or microinvasive primary tubo-ovarian malignancy and STIC were identified in approximately one in ten women undergoing RRSO. Most positive cases represented occult invasive or microinvasive malignancy, and BRCA1 c.5266dupC emerged as the dominant recurrent regional variant.

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proteins

2026-07-22 | Prevalence and Independence of p53 Signatures and β-Catenin Signatures in Risk-Reducing Salpingo-Oophorectomy Specimens.

Clusters of epithelial cells of the fallopian tube exhibiting aberrant p53 expression, termed "p53 signatures," are detected at a relatively high frequency and have been regarded as putative precursors of high-grade serous carcinoma (HGSC). In contrast, the recently proposed "β-catenin signature" represents a distinct tubal epithelial alteration characterized by the aberrant expression of β-catenin, the biological significance of which remains unclear. To clarify the frequency and spatial relationship between the two lesions, we analyzed 30 consecutive risk-reducing salpingo-oophorectomy specimens from BRCA1/2 mutation carriers using the sectioning and extensively examining the fimbriated end protocol and performed immunohistochemical evaluation for p53, β-catenin, and Ki-67. p53 signatures and β-catenin signatures were each identified in seven cases (23%). Two cases (6.7%) harbored both lesions; however, no spatial overlap or histological continuity was observed. Neither lesion demonstrated significant associations with BRCA mutation subtype, age, body mass index, or parity. Furthermore, no cases showed serous tubal intraepithelial lesion, serous tubal intraepithelial carcinoma, or HGSC. These findings suggest that p53 signatures and β-catenin signatures may represent distinct localized epithelial alterations in the fallopian tube, although further molecular and spatial analyses are required to clarify their biological relationship.

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2025-12-30 | Early Detection and Prevention of Ovarian Cancer.

Background/Objectives: Epithelial ovarian cancer (EOC) encompasses ovarian, fallopian tube and peritoneal malignancies. It is a deadly disease and is rarely cured when diagnosed at advanced stages. Early-stage disease is often curable, but clinicians and researchers have been stymied in their attempts to reliably screen for this disease, even in high-risk populations. Effective prevention of ovarian cancer is usually limited to the use of combined oral contraceptives and removal of the ovaries and fallopian tubes. Methods and Results: We aim to review the current guidelines and the evidence reported for both the early detection and prevention of ovarian cancer. Novel imaging techniques, biomarkers, and surgical advances will be discussed. Conclusions: This review will offer (a) an understanding of the epidemiology of EOC (b) analysis and a discussion of relevant molecular markers that might be exploited for more accurate early detection (c) medical and surgical methods to prevent ovarian cancer.

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2025-05-28 | Efficacy and safety data from Ph1b, dose optimization trial of two doses of TH1902 (sudocetaxel zendusortide), a novel SORT1-targeting peptide drug conjugate (PDC), administered weekly vs q3weekly in patients (pts) with advanced ovarian cancer.

e15113 Background: TH1902 is a novel PDC that targets SORT1 receptor, which is highly expressed in many solid tumors, including ovarian cancer (OVC). Via SORT1 receptor's normal trafficking function, rapid internalization and release of the docetaxel payload is achieved, resulting in higher intracellular concentrations compared to docetaxel alone. This PDC has a unique multimodal MOA, with an improved efficacy and safety profile in heavily pretreated OVC pts. Data from parts 1&2 of this Ph I study (i.e. q21 day administration of TH1902) were previously reported. An amendment to this study was implemented to evaluate if TH1902 weekly administration for 3 weeks q28days could improve both safety and efficacy. PK parameters and other biomarkers were also evaluated. Methods: Primary Ph1 objective was to characterize the safety/tolerability of TH1902. In Part 3, TH1902 was administered weekly in two cohorts: Arm A (1.75 mg/kg) and Arm B (2.50 mg/kg) on D1, D8, D15 q28 days. Doses were chosen based on safety and PK data from Parts1&2 (200-300 mg/m 2 D1 q21 days). A minimum of 6 evaluable pts was recruited in each cohort and consisted of heavily pretreated (≤8 lines of previous therapy), high grade serous OVC pts, including high grade peritoneal/fallopian tube/endometrioid cancer, who were resistant to both platinum and 1 line of taxane. Pts were followed for 12 weeks to evaluate safety, dose limiting toxicities (DLTs), tumor response, and CA125 levels. Results: 7 and 6 pts were recruited to Arm A and Arm B respectively. Neither arm had any observed DLTs. Safety profile of weekly administration was improved compared to q3weekly, with no ≥Gr 3 neuropathy, ocular or neutropenia TRAEs. At the 1.75 mg/kg/wk dose, minimal efficacy was observed with no tumor shrinkage. One pt had a maximum CA125 reduction of -34%. At the 2.50 mg/kg/wk dose, 3/6 pts had tumor shrinkage, with 2 pts achieving a 27% and 25% RECIST 1.1 reduction, and one of these 2 patients having complete resolution of a target lesion in liver. 4/6 pts on Arm B also had reductions in CA125 (15-57%). Arm A mean duration on treatment was 7.6 weeks vs 10.25 weeks on Arm B. All patients in Arm B received 2-4 cycles of TH1902 and were evaluable for efficacy. PK analyses, done at C1D1, C1D15 and C2D1 in both arms, demonstrate dose proportionality and a linear dose relationship. Conclusions: Weekly administration of TH1902 resulted in an improved safety profile, with no DLTs, few ≥Gr 3 TRAEs, and no ≥Gr 3 neuropathy, ocular or neutropenia events. An emerging efficacy signal in the higher dose arm suggests a dose response. Two additional monotherapy doses will be explored in the proposed amendment (i.e. 3.33 and 3.90 mg/kg/wk) to establish MTD and the optimal monotherapy dose for expansion cohorts. Clinical trial information: NCT04706962 .

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2025-02-16 | Estimating high-grade serous fallopian tubal carcinoma in the era of tubal hypothesis.

In the era of the serous tubal intraepithelial carcinoma hypothesis, investigation continues as to what proportions of high-grade serous tubo-ovarian carcinomas originate in the distal fallopian tube versus in the ovary. In this retrospective cohort study of 118,619 patients with high-grade serous tubo-ovarian carcinoma identified in the Commission-on-Cancer's National Cancer Database from 2004 to 2021, a diagnosis shift from high-grade serous ovarian carcinoma to high-grade serous fallopian tubal carcinoma occurred from 2004 to 2018 that the proportional distribution of high-grade serous fallopian tubal carcinoma increased 6.1-fold from 4.5% in 2004 to 27.6% in 2018 (p-trend < .001). This rapid diagnosis shift from high-grade serous ovarian carcinoma to high-grade serous fallopian tubal carcinoma reached a plateau at 2018, followed by steady proportional distribution of high-grade serous fallopian tubal carcinoma among the high-grade serous tubo-ovarian carcinomas for 4 consecutive years (27.6% in 2018 to 28.0% in 2021, p-trend = .801). The average rate of tubal carcinomas during this post-plateau period was 27.7%. In conclusion, the diagnosis shift in the primary site of high-grade serous tubo-ovarian carcinoma from the ovary to the fallopian tube may have ended in the late 2010s. After the implementation of College of American Pathologists diagnosis criteria, 1 in 3 to 4 high-grade serous tubo-ovarian carcinomas were classified as of fallopian tube origin.

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2024-09-30 | Mutant p53 Misfolding and Aggregation Precedes Transformation into High-Grade Serous Ovarian Carcinoma.

High Grade Serous Ovarian Cancer (HG-SOC), the most prevalent and aggressive gynecological malignancy, is marked by ubiquitous loss of functional p53, largely due to point mutations that arise very early in carcinogenesis. These mutations often lead to p53 protein misfolding and subsequent aggregation, yet the alterations in intracellular p53 dynamics throughout ovarian cancer progression remain poorly understood. HG-SOC originates from the fallopian tube epithelium, with a well-documented stepwise progression beginning with early pre-malignant p53 signatures. These signatures represent largely normal cells that express and accumulate mutant p53, which then transform into benign serous tubal intraepithelial lesions (STIL), progress into late pre-malignant serous tubal intraepithelial carcinoma (STIC), and ultimately lead to HGSOC. Here, we show that the transition from folded, soluble to aggregated mutant p53 occurs during the malignant transformation of benign precursor lesions into HGSOC. We analyzed fallopian tube tissue collected from ten salpingo-oophorectomy cases and determined the proportion of cells carrying soluble versus mis-folded/mutant p53 through conformation-sensitive staining and quantification. Misfolded p53 protein, prone to aggregation, is present in STICs and HG-SOCs, but notably absent from preneoplastic lesions and surrounding healthy tissue. Overall, our results indicate that aggregation of mutant p53 is a structural defect that distinguishes preneoplastic early lesions from late premalignant and malignant ones, offering a potential treatment window for targeting p53 aggregation and halting ovarian cancer progression.

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antibodies

2026-05-28 | A single-arm, phase 2 study of neoadjuvant mirvetuximab soravtansine and carboplatin for FRα-expressing advanced-stage serous epithelial ovarian, fallopian tube, or primary peritoneal cancer (M25-231; NCT06890338; GOG-3115).

TPS5633 Background: Folate receptor alpha (FRα) has limited expression on normal tissues but is highly expressed in most high-grade serous epithelial ovarian cancers (EOC), making it an attractive therapeutic target. Mirvetuximab soravtansine (MIRV), an antibody-drug conjugate targeting FRα, has demonstrated efficacy and manageable safety in recurrent, FRα-expressing EOC when used as monotherapy. Additionally, a phase 1b/2 study (IMGN853-0402) of MIRV + carboplatin showed promising clinical activity in patients with platinum-sensitive ovarian cancer who had tumor recurrence after platinum-based chemotherapy. The safety and efficacy of neoadjuvant MIRV + carboplatin in newly diagnosed, advanced-stage FRα-expressing high-grade serous ovarian cancer (HGSOC) remains unknown. Methods: This single-arm phase 2 trial will evaluate the safety and efficacy of MIRV + carboplatin in newly diagnosed patients with advanced-stage (Stage III/IV), FRα-expressing (≥75% tumor cells with ≥2+ membrane intensity per the VENTANA FOLR1 (FOLR1-2.1) RxDx Assay [Roche Diagnostics]) HGSOC. Approximately 140 patients (aged ≥18 years) will be enrolled; 5 patients were enrolled as of January 23, 2026. Patients will receive ≤6 cycles of MIRV (6 mg/kg adjusted ideal body weight) and carboplatin (AUC 5) intravenously every three weeks before interval debulking surgery (IDS), with a total of ≤9 cycles pre- and post-IDS. IDS suitability will be evaluated radiologically, and all eligible patients, including those with progressive disease (PD), will undergo IDS after Cycle 3 Day 1. IDS-ineligible patients may receive ≤3 additional cycles and undergo repeat imaging to assess IDS suitability. Patients with complete response (CR), partial response (PR), or stable disease will resume MIRV + carboplatin 3–6 weeks post-IDS following radiologic assessment. At the treating physician’s discretion, bevacizumab may be added post-IDS and standard-of-care maintenance therapy may begin ≥21 days after MIRV + carboplatin ± bevacizumab completion. Imaging will occur every 9 weeks after IDS (for those who undergo IDS) or last radiologic tumor assessment (for those who do not) until 1 year from the first dose of study treatment and then every 12 weeks until PD, death, or withdrawal of consent. The primary endpoint is objective response (OR), defined as best overall response of radiographic CR or PR assessed by Independent Central Review (ICR) per Response Evaluation Criteria in Solid Tumors v1.1 prior to initiation of subsequent anticancer therapy (including IDS). Secondary endpoints include OR by investigator (INV), disease control by ICR and INV, IDS, extent of cytoreduction at the time of IDS, cancer antigen 125 response, progression-free survival by INV, and patient-reported outcomes (NFOSI-18). Clinical trial information: NCT06890338 .

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2026-05-27 | NAPISTAR 1-01: Results of phase 1 dose escalation of monotherapy with TUB-040, a novel NaPi2b-targeting exatecan ADC, in patients (pts) with platinum-resistant ovarian cancer (PROC).

5513 Background: NaPi2b is overexpressed in high-grade serous ovarian cancer and non-small cell lung cancer (NSCLC). TUB-040 is a DAR8 ADC targeting NaPi2b, comprising a humanized Fc-silenced IgG1 mAb conjugated to exatecan via a cleavable, cysteine-selective, stable, solubility-mediating P5 linker providing excellent stability and biophysical ADC properties. In preclinical studies, TUB-040 induces potent antigen-specific cytotoxicity and demonstrates strong bystander activity. Methods: NAPISTAR 1-01 is a phase 1/2a study in biomarker-unselected pts with PROC and NSCLC. TUB-040 was administered Q3W in dose escalation (range 0.5-5.3 mg/kg) to pts with PROC until progression or unacceptable toxicity. Results: As of Dec 1, 2025, 67 PROC pts received TUB-040 for a median of 10 cycles (1-25), median duration of exposure was 213 days (21-546), and 42 (63%) pts were ongoing. Median age: 62 years (34-81), ECOG PS 0-1, median prior lines: 4 (1-7), prior treatment included bevacizumab (84%), PARPi (76%), and mirvetuximab soravtansine (13%). Between dose levels 1.67-3.3mg/kg (N=46), the most common all-grade TEAEs were nausea (78%), fatigue (54%), neutropenia (43.5%), anemia (37%), constipation (34%), diarrhea (33%), vomiting (28%), alopecia (28%), and decreased appetite (26%). Gr≥3 heme TEAEs by dose are in Table 1. There were no fatal TEAEs or treatment discontinuations due to TEAEs. Three pts (6.5%) experienced Gr1 pneumonitis, which resolved. Between dose levels 1.67–3.3 mg/kg, 46 pts were evaluated for efficacy. The uORR was 63% [95% CI, 47.5-77.2] and cORR was 60.9% [95% CI, 45.3-75.1] (RECIST; v1.1), including two cCRs. Responses by dose are in Table 1. The majority of responses, 90% (26/29), were ongoing. Disease control rate was 96% [95% CI, 85.2-99.5]. Among CA-125 evaluable pts (N=42), CA-125 response occurred in 81% (34/42) [95% CI, 65.6-91.5]. cORRs were similar across subgroups, including: ≥4 prior lines of therapy (cORR=71%), prior exposures to bevacizumab (62%), mirvetuximab soravtansine (63%) or PARPi (67%). Five pts with stable disease remain on treatment and eligible for response. Conclusions: TUB-040 was well tolerated with promising clinical activity at low doses, offering a potential new treatment option with a differentiated, favorable benefit–risk profile and a wide therapeutic window in PROC pts. Dose optimization is currently ongoing. Clinical trial information: NCT06303505 . 1.67 mg/kg (N=10), n (%) 2.1 mg/kg (N=12), n (%) 2.50 mg/kg (N=12), n (%) 3.3 mg/kg (N=12), n (%) Total (N=46), n (%) Complete response 1 (10) 0 1 (8) 0 2 (4) Partial response 6 (60) 7 (58) 7 (58) 6 (50) 26 (57) Stable disease 2 (20) 5 (42) 3 (25) 6 (50) 16 (35) Progressive disease 1 (10) 0 1 (8) 0 2 (4) Overall responses (PR + CR) 7 (70) 7 (58) 8 (67) 6 (50) 28 (60.9) Gr≥3 neutropenia 0 2 (17) 4 (33) 6 (50) 12 (26) Gr≥3 anemia 0 0 1 (8) 5 (42) 6 (13) Gr≥3 thrombocytopenia 0 0 1 (8) 1 (8) 2 (4)

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2026-05-27 | Phase 1 basket study of telisotuzumab adizutecan (Temab-A, ABBV-400), a c-Met protein–targeting antibody-drug conjugate: Results from patients with platinum-resistant ovarian/primary peritoneal/fallopian tube cancer (PROC).

5514 Background: c-Met protein is expressed in several tumor types, including PROC, and is linked with poor clinical outcomes. Temab-A comprises a c-Met protein-targeting antibody conjugated to a topoisomerase 1 inhibitor. Phase 1 studies evaluating Temab-A monotherapy in solid tumors showed antitumor activity and a manageable safety profile (NCT05029882, NCT06084481). Here, we report on the efficacy and safety of Temab-A in PROC. Methods: This phase 1, open-label basket study (NCT06084481) enrolled patients (pts) ≥18 years with histologically/cytologically confirmed recurrent PROC, with Eastern Cooperative Oncology Group performance score ≤1. Pts must have had measurable disease per investigator-assessed RECIST v1.1 criteria, have had platinum-resistant disease, and have received ≥1 but ≤5 prior lines of systemic therapy, with ≤2 prior therapies since the development of platinum resistance. Pts received Temab-A at 2.4 mg/kg every 3 weeks. Primary endpoints were safety and efficacy. Results: As of Sept. 11, 2025, 41 pts with PROC received Temab-A. Tumor histology included serous carcinoma (n=26), clear cell carcinoma (n=7), and other rare histologies (n=8). The median age was 64 years (range 43–89), and the median number of prior lines of systemic therapy was 3 (range 1–6). Median follow-up was 5.1 months. Objective response rate (ORR) was 37%. Duration of response, progression-free survival, and overall survival were immature at data cutoff. Efficacy data are shown in the Table. The most common treatment-related adverse events (TRAEs) of any Grade (G) included anemia (59%), nausea (59%), and fatigue (39%); G ≥3 TRAEs occurring in ≥10% of pts were anemia (34%), neutrophil count decreased (17%), and white blood cell count decreased (15%). The adjudicated interstitial lung disease/pneumonitis rate was 5% (G1, n=2). TRAEs led to treatment discontinuation in 5%, dose interruption in 39%, and dose reduction in 37% of pts. There were no TRAEs that led to death. Temab-A pharmacokinetics in pts with PROC were consistent with those in other tumor types. Exploratory biomarker analyses are ongoing. Conclusions: Temab-A had a manageable safety profile and showed antitumor activity in pts with PROC. Clinical trial information: NCT06084481 . Efficacy of Temab-A. a . Outcome Pts with PROC (N=41) Best overall response, n (%)Complete responsePartial responseStable diseaseProgressive diseaseNot assessed b 019 (46)16 (39)5 (12)1 (2) Objective response rate c , n (%)95% CI 15 (37)22, 53 Clinical benefit rate c , n (%)95% CI 35 (85)71, 94 a Responses were assessed by investigators per RECIST v 1.1 criteria. b Pts without postbaseline scan. c Confirmed. CI, confidence interval.

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2026-04-01 | Pertuzumab and Trastuzumab in Patients With ERBB2/3 -Altered Urothelial or Ovary/Fallopian Tube Cancer: Results From the Targeted Agent and Profiling Utilization Registry Study

PURPOSE TAPUR is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and genomic alterations. Results of two cohorts of patients with urothelial (UC) or ovarian/fallopian tube cancer (OC/FTC) with ERBB2/3 alterations treated with pertuzumab plus trastuzumab (P + T) are reported. METHODS Eligible patients had advanced cancer, measurable disease (RECIST), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, tumors with ERBB2/3 alterations, and no standard treatment options. The primary end point was disease control (DC), defined as objective response (OR) or stable disease (SD) of at least 16+ weeks duration. Simon's two-stage design is based on a null DC rate of 15% versus 35% (power = 0.85; α = .10). Secondary end points included OR, progression-free survival (PFS), overall survival (OS), duration of response, duration of SD, and safety. RESULTS Patients with UC (n = 28) or OC/FTC (n = 25) with ERBB2/3 alterations were enrolled from March 2017 to June 2023. In the UC cohort, the DC and OR rates were 37% (90% CI, 24 to 100) and 25% (95% CI, 11 to 45), respectively. The null hypothesis of 15% DC rate was rejected ( P = .005). In the OC/FTC cancer cohort, the DC and OR rates were 23% (90% CI, 9 to 100) and 8% (95% CI, 1 to 26), respectively. The null hypothesis of 15% DC rate was not rejected ( P = .35). Six patients had at least one grade 3-5 adverse event (AE) or serious AE at least possibly related to treatment. CONCLUSION The combination of P + T met prespecified criteria to declare a signal of activity in patients with UC with ERBB2/3 alterations, but not in patients with OC/FTC.

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2026-01-01 | Mirvetuximab Soravtansine: Mechanism of Action, Clinical and Translational Science

Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate (ADC) composed of the DM4 payload conjugated to a folate receptor α (FRα)-targeting antibody via the cleavable sulfo-SPDB linker. MIRV targets and binds to FRα with high affinity and specificity, releasing the DM4 payload intracellularly following MIRV-FRα complex internalization and degradation. DM4 and its metabolite S-methyl-DM4 suppress microtubule dynamic instability, which triggers cell cycle arrest and apoptosis. Selective FRα-overexpression in ≥ 90% of epithelial ovarian tumor cells and its ability to internalize large molecules make it a highly attractive ADC target for epithelial ovarian cancers (including primary peritoneal and fallopian tube cancers). Although up to 80% of patients initially respond to platinum-based therapies, the majority of tumors will recur and become platinum-resistant. Unfortunately, platinum-resistant ovarian cancer (PROC) carries a poor prognosis with an overall survival of 12-14 months from the time of platinum-resistance, and prior to MIRV approval in 2022, little had changed in treatment options for decades. The MIRV Phase 3 registrational trial (MIRASOL) showed superiority of MIRV vs. chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan) in patients with high (≥ 75%) FRα-expression PROC, showing an objective response rate of 42% versus 16%, a median progression-free survival of 5.6 versus 4.0 months, and an overall survival of 16.5 versus 12.8 months. Here, we briefly review MIRV mechanism of action, pharmacokinetics, pharmacodynamics, and key clinical efficacy and safety data.

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cell therapies

2025-12-15 | Pregnancy with vitrified oocytes after fertility sparing surgery in a patient with fallopian tube cancer and a BRCA2 mutation: A case report and literature review.

High-grade carcinomas affecting the ovary or peritoneum may originate from the epithelium of the fallopian tubes. Whilst gynecological cancers are more frequent in post-menopausal patients, 12.1% of ovarian malignancies are diagnosed in patients of childbearing age, aged <45 years. There is not enough data to provide an accurate estimate on the incidence of relapse, the chance of pregnancy and outcomes of assisted reproduction and fertility-sparing surgery techniques in young patients with ovarian cancer. Moreover, there is currently a lack of data regarding fertility preservation techniques for patients with cancer of the fallopian tubes. To the best of our knowledge, the present report describes the first live newborn birth using vitrified oocytes retrieved before fertility-sparing surgery for primary fallopian tube cancer (stage IC1) in a patient with a BRCA2 mutation. Furthermore, a narrative review of literature from 2000-2024 from several online databases was performed to identify articles involving patients with fallopian tube cancer and BRCA mutations, who underwent fertility preservation with vitrified oocytes and fertility-sparing surgery. A total of 44 manuscripts were retrieved, with only two articles reporting data on pregnancy with vitrified oocytes after fertility-sparing surgery, and 3 cases included. Whilst more research is required for assisted reproductive technology and ovarian cancer, and for the elucidation of the role of BRCA mutations on fertility, the present report aims to provide impetus to further research in this field.

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2025-12-01 | Natural Killer (NK) Cell-Based Therapies Have the Potential to Treat Ovarian Cancer Effectively by Targeting Diverse Tumor Populations and Reducing the Risk of Recurrence

Ovarian cancer is the sixth leading cause of cancer-related deaths among women in the United States. This complex disease arises from tissues such as the ovarian surface epithelium, fallopian tube epithelium, endometrium, or ectopic Müllerian components and is characterized by diverse histological and molecular traits. Standard treatments like surgery, chemotherapy, and radiation have limited effectiveness and high toxicity. Targeted therapies, including poly (ADP-ribose) polymerase PARP inhibitors, anti-angiogenics, and immune checkpoint inhibitors (ICIs), face obstacles such as adaptive resistance and microenvironmental barriers that affect drug delivery and immune responses. Factors in the tumor microenvironment, such as dense stroma, hypoxia, immune suppression, cancer stem cells (CSCs), and angiogenesis, can reduce drug efficacy, worsen prognosis, and increase the risk of recurrence. Research highlights impaired immune function in ovarian cancer patients as a contributor to recurrence, emphasizing the importance of immunotherapies to target tumors and restore immune function. Preclinical studies and early clinical trials found that natural killer (NK) cell-based therapies have great potential to tackle ovarian tumors. This review explores the challenges and opportunities in treating ovarian cancer, focusing on how NK cells could help overcome these obstacles. Recent findings reveal that engineered NK cells, unlike their primary NK cells, can destroy both stem-like and differentiated ovarian tumors, pointing to their ability to target diverse tumor types. Animal studies on NK cell therapies for solid cancers have shown smaller tumor sizes, tumor differentiation in vivo, recruitment of NK and T cells in the tumor environment and peripheral tissues, restored immune function, and fewer tumor-related systemic effects-suggesting a lower chance of recurrence. NK cells clinical trials in ovarian cancer patients have also shown encouraging results, and future directions include combining NK cell therapies with standard treatments to potentially boost effectiveness.

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2025-11-04 | Salpingectomy in individuals at high risk for tubo-ovarian cancer: consensus and precaution.

Tubo-ovarian carcinoma, particularly high-grade serous carcinoma, is one of the most lethal gynecologic malignancies, largely due to its late-stage diagnosis and lack of effective screening strategies. For individuals with hereditary pathogenic variants in genes associated with ovarian cancer such as BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, PALB2, and Lynch syndrome-associated genes, the National Comprehensive Cancer Network recommends risk-reducing salpingo-oophorectomy, which has been shown to decrease mortality. However, premenopausal oophorectomy can result in substantial quality-of-life impairments, and as a result, many high-risk individuals delay or forego risk-reducing salpingo-oophorectomy despite its proven mortality benefit. The discovery that most high-grade serous carcinomas originate in the fallopian tubes has led to interest in a novel preventive strategy: risk-reducing salpingectomy followed by delayed oophorectomy in high-risk individuals. In this clinical opinion, we describe that while risk-reducing salpingectomy with delayed oophorectomy has been associated with improved menopause-related quality of life and reduced cancer worry, its efficacy in cancer risk reduction has not been established. We explain the importance of offering risk-reducing salpingectomy with delayed oophorectomy within clinical trials whenever possible.

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2025-07-04 | Single cell functional immunogenomics of the fallopian tube reveals a precursor immune surveillance network for ovarian cancer prevention

ABSTRACT The fallopian tube (FT) is increasingly recognized as the site of origin for high-grade serous ovarian cancer (HGSOC), yet its immune landscape and potential role in tumor surveillance remain poorly understood. Here, we employ single-cell RNA sequencing (scRNA-seq) and paired single-cell T-cell receptor sequencing (scTCR-seq) to profile tissue-resident memory-like T cells (TRMLs) from matched non- cancerous FT, metastatic omental tumors, and peripheral blood in HGSOC patients. Surprisingly, we identify a substantial clonal and functional overlap between TRMLs from non-cancerous FT and tumor- infiltrating TRMLs, with 18.4% of tumor TRML clonotypes being shared with FT TRMLs, significantly exceeding overlap with circulating T cells. Shared TCR clonotypes are preferentially enriched in exhausted CD8+ T cells (CD8-Tex) and proliferative exhausted CD8+ subsets, suggesting prior antigenic exposure. Notably, we identify a previously uncharacterized CD8+ SIK3-high subset enriched in tumors, with gene expression signatures implicating epigenetic plasticity and metabolic adaptation. Functionally, non-cancerous FT-derived TRMLs recognize autologous tumor antigens, as evidenced by robust IFN-γ responses in tumor organoid co-culture assays and CD137 upregulation. Whole-genome and transcriptomic analyses reveal shared somatic mutations between the FT and tumor, supporting the FT as the tumor’s evolutionary origin. Predicted tumor neoantigens elicit TRML responses in the non-cancerous FT, and single-cell TCR profiling confirms that neoantigen-reactive T cells in FT share clonotypes with tumor-infiltrating TRMLs, further reinforcing their role in early immune surveillance. Importantly, FT-derived TRMLs exhibit lower exhaustion signatures than their tumor counterparts, suggesting their potential as a preferable source for adoptive T cell therapies. Our findings uncover a precursor immune surveillance network in the FT and provide a rationale for leveraging FT-resident T cells in cancer immunotherapy and prevention.

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2024-03-04 | Abstract A047: Modeling the role of the fallopian tube in the prevention and spread of high grade serous cancer using a multi-organ platform

Abstract It is now recognized that a large percentage of high grade serous ovarian cancers arise in the fallopian tube and colonize the ovary as the primary metastatic step. One of the risk factors associated with ovarian cancer is the lifetime number of ovulations. Few models are currently available that allow the process of ovulation and the development of ovarian cancer to be studied. To address this gap, our team developed a microphysiological platform called PREDICT-multi-organ-system (MOS). PREDICT-MOS contains 30 wells for culturing organs and 60 pumps with precisely controlled flow rates. Human fallopian tube tissue can be grown in an air-liquid interface, while murine ovaries can be engineered to ovulate while producing and secreting physiological concentrations of hormones and proteins over the entire process of ovulation. Importantly, these secreted factors are contained in the device within the media and can therefore precisely model local concentration gradients and temporal exposure of the human fallopian tube tissues. First, we uncovered that the ovary secretes versican during the cycle to enhance ovarian migration, adhesion, and expansion within the ovarian microenvironment. We revealed that fallopian tube tumor cells stimulate the ovary to produce testosterone, which enhanced fallopian tube invasion and stem cell marker expression. Next, we profiled the expression of secreted extracellular vesicles that are produced by the fallopian tube on the platform. Extracellular vesicles may provide a new form of liquid biopsy, but understanding the cargo expressed from normal cells is critical for understanding the importance of cancer EV’s during progression. Finally, we have engineered the platform to allow for real-time invasion using an insert technology and a modified pump that allows for interaction between the organs. Overall, the integration of organ-on-chip technology with key human tissues allows for the in-depth analysis of the role of ovulation in the onset and spread of high-grade serous cancer from the fallopian tube. Citation Format: Joanna Burdette. Modeling the role of the fallopian tube in the prevention and spread of high grade serous cancer using a multi-organ platform [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A047.

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2026-02-06 | Pembrolizumab and epigenetic modification with azacitidine reshapes the tumor microenvironment of platinum-resistant epithelial ovarian cancer: a phase 2 non-randomized clinical trial

BACKGROUND: Epigenetic modulators may sensitize platinum-resistant ovarian cancer (PROC) to immune checkpoint inhibition by reprogramming the tumor microenvironment. METHODS: We report clinical and translational findings from a phase II non-randomized study of pembrolizumab and oral azacitidine in 34 women with PROC (NCT02900560). Key eligibility criteria included age 18 years or older, performance status of 0-1, measurable disease, platinum-resistant disease and histologically confirmed epithelial ovarian cancer, fallopian tube carcinoma or primary peritoneal carcinoma. Primary endpoints included safety, tolerability, overall response rate (ORR) and disease control rate (DCR). Secondary endpoints included CA-125 response. The effect of combined epigenetic and immunotherapy was evaluated by transcriptomic analyses of 72 serially biopsied tumors. RESULTS: We show that the combination is moderately well tolerated and most common grade 3-4 adverse events are gastrointestinal side effects and anemia. ORR is 2.9% and DCR is 50%; with 3 of the 27 evaluable patients attaining a CA-125 response. Differential gene expression analyses reveal an upregulation of inflammatory and cytolytic genes and co-inhibitory checkpoints 6 weeks on-therapy. Upregulation of interferon signaling, antigen presentation and immune cell adhesion and migration gene sets are prominent on-therapy, together with an increase in density of CD8 + T-cells. Patients with a CA-125 and/or clinical response show an enrichment of adaptive and conserved immune response gene sets on-therapy. CONCLUSIONS: Our findings highlight the potential of epigenetic modulators to re-shape the tumor microenvironment of PROC toward a more inflammed phenotype and may point to approaches to augment immunotherapy response.

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2025-05-13 | Human Papillomaviruses and Malignant Neoplasms of the Female Upper Reproductive Tract: A Comprehensive Review of the Literature

Malignancies of the female upper reproductive tract, especially endometrial and ovarian cancers, consist a significant burden for women worldwide. The possible etiopathogenetic role of chronic human papillomavirus (HPV) infection in the female upper genital tract carcinogenesis is neither clearly established not completely understood. Therefore, we performed a literature review through PubMed and SCOPUS electronic databases about the prevalence of HPV DNA in endometrial, primary fallopian tube, ovarian and primary peritoneal cancers, as well as uterine sarcomas. The present investigation covered 35 studies from different countries of various continents. Overall, HPV prevalence was approximately 15% in all the above cancers. HPV DNA was isolated from 11%, 0%, 0% and 14% of endometrial carcinomas, uterine sarcomas, primary fallopian tube cancers and ovarian malignant neoplasms, respectively. No relevant studies on primary peritoneal cancers were retrieved. The predominant HPV strain from all tumors of the upper female reproductive tract, regardless of the tumor site, was mostly HPV-16, followed by HPV-18. HPV DNA was identified exclusively from subtypes HPV-6, HPV-11, HPV-16, HPV-18, and HPV-33, which are responsible for the development of not only cervical cancer, but also of condylomata acuminata. The findings of the present review indicate that HPV vaccination might prove to be a useful strategy in the prevention HPV-related carcinomas of the upper genital tract in women.

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2025-05-08 | Development of a nano-vaccine for high-grade serous ovarian cancer.

High-Grade Serous Carcinoma (HGSC) is characterised by aggressive malignant tumours and poor prognosis accounting for 75% of ovarian cancer. Conventional treatments often result in relapse, with a need for innovative therapeutic approaches. This study aimed to develop and evaluate a DNA vaccine targeting the preferentially expressed antigen of melanoma, PRAME, a cancer tumour antigen (CTA) overexpressed in HGSC. PRAME demonstrated the highest differential gene expression between normal fallopian tubes and HGSC tumour tissues in a range of patient datasets. The PRAME DNA was condensed by the cationic cell-penetrating peptide RALA to form nanoparticles (NPs). These self-assembling NPs exhibited a mean hydrodynamic size <150 nm and zeta potential >10 mV at N : P ratios ≥4 with ≤3% free DNA. The NPs successfully transfected NCTC-929 and DC 2.4 cells with PRAME overexpression, with negligible cytotoxicity. Vaccination with the NPs in vivo elevated CD4+ and CD8+ T-cell activation with increased expression of INF-γ and IL-2 cytokines. Vaccination also significantly improved survival rates in a PRAME-expressing tumour model in vivo. This study demonstrated the utility of a PRAME-targeted DNA vaccine for HGSC treatment which warrants further investigation.

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2025-04-21 | Abstract 6517: Extracellular vesicles derived from vaginal bacteria initiate the progression of early phase ovarian carcinoma at fallopian tubes

Abstract [Objective] Microbiota contributes to cancer hallmarks, but the relationship vaginal bacteria and ovarian cancer are entirely unclear. Extracellular vesicles (EVs), including exosomes, play a crucial role in cancer biology, and bacteria secrete EVs, named bacterial EVs (bEV). Recent understanding revealed that high-grade serous carcinoma (HGSC) has raised from fallopian tube epithelial cells (FT cells) but the detailed mechanism how FT cells acquired malignant potential is largely unknown. This study aimed to elucidate the mechanism of initiation of early-phase ovarian carcinoma at fallopian tubes via vaginal bEV. [Methods] For selecting promising bacteria, vaginal bacterial 16s sequencing data were referred to, and the data from 181 patients with ovarian tumors were analyzed. bEVs were directly collected from patients’ fallopian tubes using cellulose nanofiber-based EV sheets (Yokoi A et al. Nat Commun. 2023), and bEV-RNA was extracted. Selected bacteria were cultured with monitoring OD values, and bEVs were isolated using the optimal serial centrifugation method. bEV-RNA were analyzed by small RNA sequencing and validated by qRT-PCR. Functional analyses were performed in vitro and in vivo, and the effect of bEVs on FT cells was investigated. [Results] Based on vaginal bacterial 16s rRNA sequencing, four indigenous common vaginal bacteria were selected. Those bacteria were successfully cultured and cryo-electron microscopy confirmed isolated bEV. Cell viability analysis showed that none of the bEVs affected the proliferation of FT cells. On the other hand, specific Lactobacillus species promoted cell motility (p &lt;0.05), especially in p53 gain-of-function (GOF) cells. Furthermore, treatment of bEV resulted the sloughed-off features of p53-GOF-FT cells on basement membrane components (p &lt;0.05). These phenotypes mimic the actual progression of FT cells implant to ovaries. In in vivo experiments, although vaginal treatment of bacterial bodies did not reach FT, bEVs were incorporated by FT cells, which were confirmed by confocal microscopy imaging. We collected bEVs on FT from 15 ovarian cancer patients using cellulose nanofiber-based EV sheets, and small RNA sequencing for bEV-RNA revealed that the profiles between HGSC and benign patients were different, and specific sequences of Lactobacillus species were detected. mRNA sequencing for FT cells treated with bEV from specific Lactobacillus species showed that gene expression was significantly altered, and IPA/GSEA analyses identified several cancer-related pathways. Target functional genes in FT cells were identified and validated by qRT-PCR. [Conclusions] These results demonstrated the unknown early mechanism of ovarian cancer development by pathogenic bEV exposure, and the new target gene alternation was identified in FT cells as the new therapeutic target. Citation Format: Akira Yokoi, Eri Asano-Inami, Kosuke Yoshida, Yukari Nagao, Masami Kitagawa, Hiroaki Kajiyama. Extracellular vesicles derived from vaginal bacteria initiate the progression of early phase ovarian carcinoma at fallopian tubes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6517.

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2025-03-07 | [Is there a place for prophylactic fimbriectomy followed by delayed ovariectomy?].

Risk reducing salpingo-oophorectomy has long been the gold standard for preventing the development of tubo-ovarian cancers in high-risk population such as BRCA1/2 mutation carriers. Although a clear survival benefit has been demonstrated of these prophylactic procedures, important side effect from the associated surgical menopause have been described. Given that recent evidence suggests that most high-grade serous carcinomas (HGSC), the majority of all ovarian carcinomas, and especially for patients with a genetic predisposition originate in the fallopian tube, where also precursor lesions such as STIC can be found, an alternative risk reduction strategy has emerged, the prophylactic fimbriectomy with delayed oophorectomy. Multiple studies have already investigated the acceptability, side effects and safety of this procedure, with promising results. And currently multiple studies are ongoing to investigate the long-term effects on sexuality and the risk of developing subsequent tubo-ovarian carcinomas. A long-term follow-up in a large population is essential given the latency of 4-5 years between precursor lesions and HGSC. In this review, we provide an overview of the current knowledge on the origin, screening, and risk-reducing surgery for the prevention of tubo-ovarian cancers in high-risk women.

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