tbuckley/cabot-search huggingface dataset:
Phase 1b study of tarlatamab in de novo or treatment-emergent neuroendocrine prostate cancer (NEPC).
Authors: Rahul Raj Aggarwal, Sylvie Rottey, Alice Bernard-Tessier, Begoña Mellado-Gonzalez, Takeo Kosaka, Walter Michael Stadler, Shahneen Sandhu, Brian Yu, Crystal Shaw, Chia-Hsin Ju, Corbin Thompson, Ana Aparicio
Journal: Journal of Clinical Oncology (2024)

5012 Background: NEPC is an aggressive form of prostate cancer with poor prognosis and no standard treatment approach. NEPC can be characterized by late, treatment-emergent transformation from adenocarcinoma to high-grade neuroendocrine carcinoma (NEC), in 10–15% of mCRPC patients (pts). DLL3 is overexpressed in high-grade NECs, including NEPC, and minimally expressed on normal tissue. Tarlatamab, a bispecific T-cell engager immunotherapy with clinical activity in small cell lung cancer (SCLC), binds DLL3 and CD3 resulting in T-cell mediated tumor lysis. Here, we report primary analysis data of tarlatamab in NEPC (NCT04702737). Methods: This is an open-label phase 1b study evaluating tarlatamab monotherapy in adult (≥18 years [y]) pts with metastatic de novo or treatment-emergent NEPC by histologic, genomic, or immunohistochemistry (IHC) criteria. The starting dose was the highest safe and tolerable dose in the phase 1 SCLC trial (NCT03319940). Safety was the primary objective; anti-tumor activity and pharmacokinetics were secondary objectives. Exploratory analysis of DLL3 expression was assessed by IHC using the Ventana SP347 assay. Results: As of 28 March 2023, 40 pts received ≥1 tarlatamab dose (1 mg step dose, 100 mg target dose). Median (range) age was 64.5 (43–83) y, prior lines of therapy was 3 (1–9), prostate specific antigen at baseline was 0.2 (0.0–5000.0) μg/L. Treatment-related adverse events (TRAE) occurred in all patients, with no fatal TRAE. Most common TRAEs were cytokine-release syndrome (CRS; 65.0%), pyrexia (52.5%) and dysgeusia (42.5%). CRS occurred primarily in treatment cycle 1; events were mostly grade 1–2 (one grade 3 event). Treatment discontinuation due to TRAE was low (7.5%). Tarlatamab serum exposures were consistent with tarlatamab SCLC studies. Objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) was 10.5% (95% CI, 2.9, 24.8); median progression free survival (mPFS) was 1.9 months (m) (95% CI, 1.7, 3.5). Retrospective DLL3 IHC analysis showed that 18 of 32 (56.3%) biopsy evaluable pts had ≥1% DLL3 tumor positivity (DLL3+). As of 24 January 2024, ORR in DLL3+ pts was 22.2% (95% CI, 6.4, 47.6); durations of response in the 4 pts with response were 25.8 m, 9.2 m, 5.5 m, 3.7 m; mPFS in DLL3+ pts was 3.75 m (95% CI, 1.87, 11.01). Efficacy is shown in Table. Conclusions: Findings from this phase 1 study of tarlatamab in pts with NEPC demonstrated manageable safety with encouraging anti-tumor activity in DLL3 expressing NEPC. Further investigation is ongoing. Clinical trial information: NCT04702737 . [Table: see text]
Unveiling the pathologic predictor in patients with metastatic hormone-sensitive prostate cancer treated with abiraterone: Intraductal carcinoma of the prostate and its subtypes.
Authors: Xinyuan Wei, Jinge Zhao, Yifu Shi, Pengfei Shen, Zhenhua Liu, Hao Zeng
Journal: Journal of Clinical Oncology (2024)

e17077 Background: Intraductal carcinoma of the prostate (IDC-P) is a distinct pathological type of prostate cancer (PCa). Its association with poor prognosis in patients has gained widespread recognition. In this study, we aimed to assess whether metastatic hormone-sensitive prostate cancer (mHSPC) patients with different IDC-P statuses and subtypes exhibited varying responses to abiraterone treatment, with the goal of exploring its potential as a predictive pathological marker. Methods: We conducted a retrospective analysis of data from 165 mHSPC patients who received abiraterone treatment. Propensity score matching (PSM) was employed to minimize the potential impact of selection bias and confounding factors. We evaluated PSA response, PSA progression-free survival (PSA-PFS), radiographic progression-free survival (rPFS), and overall survival (OS) based on IDC-P status and its subtypes (pattern 1: loose cribriform or micropapillary; pattern 2: solid or dense cribriform). We also conducted subgroup analyses to explore their predictive value in different patient populations. Results: Following PSM, a cohort of 108 mHSPC patients was established, among whom IDC-P was confirmed in 54 out of 108 (50%) individuals. Of these, 12/54 (22.2%) exhibited IDC-P pattern 1, while 42/54 (77.8%) had IDC-P pattern 2. The median follow-up duration for the entire cohort was 32.5 months, with median PSA-PFS, rPFS, and OS values of 24.3 months, 31.9 months, and not reached, respectively. No statistically significant difference was observed in PSA responses among patients with different IDC-P statuses. However, patients with IDC-P demonstrated poorer survival outcomes (PSA-PFS: 18.6 vs. NR months, p = 0.002; rPFS: 23.6 vs. NR months, p = 0.020). Patients with IDC-P pattern 1 exhibited clinical outcomes similar to those without IDC-P, whereas patients with IDC-P pattern 2 had significantly worse prognosis compared to those without IDC-P (PSA-PFS: 18.6 vs. NR months, p = 0.002; rPFS: 22.4 vs. NR months, p = 0.010). Subgroup analyses revealed a significant association between IDC-P pattern 2 and poorer prognosis across most population subgroups. Conclusions: Our study assessed the predictive value of IDC-P and its subtypes in prostate biopsy specimens of mHSPC patients undergoing abiraterone treatment. IDC-P, particularly IDC-P pattern 2, serves as an adverse prognostic indicator in these patients. Therefore, routine reporting of IDC-P and its pattern is important for treatment strategy making for prostate cancer patients.
Phase III, double-blind, placebo-controlled, 2-cohort, randomized study of saruparib (AZD5305) in combination with new hormonal agents in patients with metastatic castration-sensitive prostate cancer with and without homologous recombination repair mutation (EvoPAR-Prostate01).
Authors: Kim N. Chi, Neeraj Agarwal, Andrew J. Armstrong, Eva Hellmis, Friederike Schlürmann, Mikio Sugimoto, Yüksel Ürün, Nianzeng Xing, Mehreteab Aregay, Julianne Lima, Didier Meulendijks, Arun Azad
Journal: Journal of Clinical Oncology (2024)

TPS5123 Background: PARP inhibitors (PARPi) in combination with new hormonal agents (NHAs) are approved for treatment of metastatic castration-resistant prostate cancer (mCRPC). PARPi utilization in earlier lines of treatment may result in greater magnitude of benefit. Saruparib is a potential best-in-class PARPi, which selectively inhibits and traps PARP1, has minimal effect on PARP2, and hence may offer an improved therapeutic window compared with currently approved nonselective PARPi. The efficacy and safety of saruparib plus NHAs for the treatment of metastatic castration-sensitive prostate cancer (mCSPC) and mCRPC are being assessed in the phase I/IIa PETRANHA study (NCT05367440). The phase III EvoPAR-Prostate01 study (NCT06120491) is evaluating the efficacy and safety of saruparib plus physician’s choice of NHA (abiraterone, darolutamide, or enzalutamide) compared with placebo plus physician’s choice of NHA in participants with mCSPC. Methods: This is a 2-cohort, 2-arm, randomized, double-blind, placebo-controlled, multicenter global study. Key eligibility criteria include age ≥18 years, histologically confirmed mCSPC ( de novo or recurrent low- or high-volume disease), ECOG PS 0-1, and confirmed, prospectively defined homologous recombination repair gene mutation (HRRm) status (defined by the presence/absence of pathogenic/likely pathogenic mutations in ≥1 of the genes BRCA1, BRCA2, ATM, CDK12, PALB2, RAD51B, RAD51C, RAD51D,and BARD1). Participants must be receiving androgen deprivation therapy throughout the study or have undergone bilateral orchiectomy, and must be suitable for treatment with NHAs. Key exclusion criteria include prior therapy with PARPi, prior chemotherapy or NHAs in the mCSPC setting (prior NHAs for localized disease permitted), and history of, or suspected, myelodysplastic syndrome/acute myeloid leukemia. Participants are allocated to either the HRRm or non-HRRm cohort based on prospective testing of both tumor tissue and circulating tumor DNA. Participants are randomized 1:1 to receive saruparib plus physician’s choice of NHA or placebo plus physician’s choice of NHA. Treatment continues until disease progression, unacceptable toxicity, or participant-initiated withdrawal. The primary endpoint is radiographic progression-free survival (rPFS), with overall survival (OS) a key secondary endpoint. Planned statistical analyses of rPFS and OS will be conducted within each cohort using a stratified log-rank test. Approximately 1,800 participants (550 HRRm; 1,250 non-HRRm) will be randomized. Enrollment began in November 2023 and is ongoing. Clinical trial information: NCT06120491 .
Prognostic implications of PSA levels at 7 months in metastatic hormone-sensitive prostate cancer treated with enzalutamide: Landmark analysis of ENZAMET (ANZUP 1304).
Authors: Ronan Andrew Mc Laughlin, Hayley Thomas, Ian D. Davis, Robert Richard Zielinski, Alastair Thomson, Thean Hsiang Tan, Shahneen Sandhu, M. Neil Reaume, David William Pook, Francis Parnis, Scott A. North, Gavin M. Marx, John McCaffrey, Raymond S. McDermott, Lisa Horvath, Mark Frydenberg, Simon Chowdhury, Kim N. Chi, Martin R. Stockler, Christopher Sweeney
Journal: Journal of Clinical Oncology (2024)

5079 Background: ENZAMET (NCT02446405) showed that enzalutamide added to testosterone suppression (TS) with or without docetaxel improves overall survival (OS) compared with TS plus standard non-steroidal anti-androgen (NSAA) in patients with metastatic hormone-sensitive prostate cancer (mHSPC). We assessed PSA levels in ENZAMET participants at 7 months after randomization to determine correlations with OS. In CHAARTED, participants with mHSPC high volume disease (HV), 20% achieved PSA ≤ 0.2 with ADT (androgen deprivation therapy) alone versus 44% with low volume disease (LV) and for HV with ADT + Docetaxel, 36% achieved PSA ≤ 0.2 vs 64% with LV. Methods: Participants were included if they were followed for at least 7 months after randomization, and had availability of PSA and outcome data. Landmark analysis at 7 months used prognostic classifiers as previously identified in SWOG 9346 and CHAARTED of PSA ≤ 0.2 and &gt; 0.2 at 7 months after initiation of therapy. Results: The total number of ENZAMET participants (pts) with PSA at 7 months of ≤0.2ng/mL was 646 of 1125 (57%): 271/562 (48%) in the NSAA arm versus 375/563 (67%) in the ENZA arm. Five-year OS for TS + NSAA (±Doc) arm PSA ≤ 0.2 = 71% vs PSA &gt; 0.2 = 36% and for TS + ENZA (±Doc) arm PSA ≤ 0.2 = 74% vs PSA &gt; 0.2 = 43%. The % of pts with PSA levels at 7 months ≤0.2ng/mL and corresponding 5-year OS outcomes by key prognostic groups (HV vs LV) ± docetaxel is shown (Table). In comparison with CHAARTED in those with HV, 37% achieved PSA ≤ 0.2 with ADT alone versus 61% with LV which increased to 55% for HV and 79% for LV respectively with addition of enzalutamide. In those with HV treated with ADT + D 39% achieved PSA ≤ 0.2 vs 58% with LV increasing to 60% for HV and 74% for LV respectively with addition of enzalutamide. Conclusions: A PSA nadir of ≤0.2 at 7 months is associated with a longer OS regardless of treatment and prognostic group (HV vs LV). Enzalutamide increased the rate of achievement of PSA &lt;0.2 for all groups. Clinical trial information: NCT02446405 . [Table: see text]
High dose chemotherapy in male patients with germ cell cancer: A population-based study by the SWENOTECA group.
Authors: Anna Jansson, Gabriella Elisabeth Cohn-Cedermark, Helene F. S. Negaard, Torgrim Tandstad, Olof Stahl, Annika Hedlund, Asa Karlsdottir, Martin Hellström, Carl Wilhelm Langberg, Camilla Sköld, Hege Sagstuen Haugnes, Ingrid Glimelius
Journal: Journal of Clinical Oncology (2024)

5040 Background: Selected patients with advanced germ cell tumors have a poor prognosis. These include patients with brain, bone or liver metastases, very elevated tumor markers or primary mediastinal tumor. High-dose chemotherapy (HDCT) with autologous stem cell support is recommended in the Swedish and Norwegian Testicular Cancer Group (SWENOTECA) guidelines in selected poor risk patients with poor response to/relapse after intense primary treatment. From the year 2011, the HDCT-regimen consisted of two cycles of carboplatin and etoposide. Our aim of this study was to evaluate survival and toxicity in patients treated with HDCT within the population-based SWENOTECA cancer care program in 2011-2021. Methods: All patients treated with HDCT according to guidelines in Sweden and Norway between 2011-2021 were included, in total 80 patients (76 non-seminoma and 4 seminoma). This reflected approximately 3% of all non-seminoma patients. HDCT was administered in three different clinical situations: delayed tumor marker decline during primary or intensified primary treatment (n=26), progressive disease during primary treatment (n=29) (defined as progressive disease within &lt;3 months from last cycle of chemotherapy), or relapse with poor prognosis (n=25). The overall survival (OS) and failure-free survival (FFS) were calculated, and the toxicity was described. Results: The 5-year overall survival (OS) and failure free survival (FFS) after HDCT was 55% and 43% respectively. HDCT due to delayed tumor marker decline had a more favorable outcome, 5-year OS of 75% and 5-year FFS of 53%. HDCT due to relapse resulted in a 5-year OS of 61% and 5-year FFS of 58%. Patients treated with HDCT due to progressive disease during primary treatment had a markedly less favorable 5-year OS of 29% and 5-year FFS of 18%. Four patients (5%) died due to treatment. The most common treatment-related grade 3-4 toxicities were infections (n=69, 86%). Conclusions: In this population-based study, we have shown that HDCT for patients with advanced germ cell cancer according to the SWENOTECA cancer care program is achievable and leads to favorable OS and FFS rates. Furthermore, even though patients that receive HDCT due to progressive disease have a relatively poor outcome, 20-30% of patients do achieve long-term survival. [Table: see text]
The silent burden: A SEER-based analysis of potential years of life lost due to genitourinary cancers in the United States (1975-2017).
Authors: Rajvi Gor, Pranav Gwalani, DHAIRYA GOR, Anand Shah, Rahul Kumar Thakur, Benjamin Adam Gartrell
Journal: Journal of Clinical Oncology (2024)

e17107 Background: Genitourinary (GU) cancers significantly impact United States (US) public health, not just in mortality but also in premature deaths. We evaluated the potential years of life lost (PYLL) due to these cancers (prostate, kidney, bladder, testicular, penile, and others) from 1975 to 2017 using the SEER database and stratified it across racial groups. Methods: From 1975 to 2017, GU cancers were identified using SEER*Stat 8.4.2 using ICD-10 CM codes. We analyzed premature deaths and calculated PYLL as [Life expectancy minus (age at diagnosis + survival time)]. Due to non-homogeneity, the Kruskal-Wallis test (α = 5%) was employed for subgroup PYLL analysis. Spearman correlation coefficient (ρ) assessed the relationship between the year of diagnosis and PYLL. Analyses were conducted using SAS OnDemand. Results: Of the 1,715,763 GU cancer cases (1975-2017), 235,279 had premature deaths, totaling 2,406,551.20 PYLL. Testicular cancer showed the highest median PYLL (33.3 years) compared to other sites, followed by penile cancer with a median PYLL of 12.2 years. Non-Hispanic (NH) Blacks had higher PYLL for prostate, kidney, ureteral, and bladder cancers (p&lt;0.05), while Hispanics had higher PYLL for penile and testicular cancers (p&lt;0.0001). ρ value for PYLL and year of diagnosis was 0.23. Conclusions: Our study reveals a substantial impact of GU cancers on premature mortality and PYLL in the US. Despite the lower prevalence, testicular and penile cancers contribute significantly to PYLL, likely related to younger age at diagnosis. Racial disparities were evident, with NH-Blacks and Hispanics experiencing higher PYLL for specific GU cancers compared to other racial groups. These findings underscore the pressing need for targeted interventions to address disparities and enhance GU cancer management and prevention outcomes. [Table: see text]
IDH1 inhibition potentiates chemotherapy efficacy in pancreatic cancer
Authors: Mehrdad Zarei, Omid Hajihassani, Jonathan J. Hue, Alexander W. Loftus, Hallie J. Graor, Faith Nakazzi, Parnian Naji, Christina S. Boutros, Vinayak Uppin, Ali Vaziri-Gohar, Akram Shalaby, John M. Asara, Luke D. Rothermel, Jonathan R. Brody, Jordan M. Winter
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is associated with a five-year overall survival rate of just 13%, and development of chemotherapy resistance is nearly universal. PDAC cells overexpress wild-type IDH1 that can enable them to overcome metabolic stress, suggesting it could represent a therapeutic target in PDAC. Here, we found that anti-IDH1 therapy enhanced the efficacy of conventional chemotherapeutics. Chemotherapy treatment induced ROS and increased TCA cycle activity in PDAC cells, along with the induction of wild-type IDH1 expression as a key resistance factor. IDH1 facilitated PDAC survival following chemotherapy treatment by supporting mitochondrial function and antioxidant defense to neutralize reactive oxygen species through the generation of alpha-ketoglutarate and NADPH, respectively. Pharmacologic inhibition of wild-type IDH1 with ivosidenib synergized with conventional chemotherapeutics in vitro and potentiated the efficacy of sub-therapeutic doses of these drugs in vivo in murine PDAC models. This promising treatment approach is translatable through available and safe oral inhibitors and provides the basis of an open and accruing clinical trial testing this combination (NCT05209074).
A phase II trial of enfortumab vedotin for locally advanced and metastatic squamous cell carcinoma of the penis.
Authors: Lance C. Pagliaro, Cassandra N. Moore, Winston Tan, Olivia Bobek, David W. Hillman, Sounak Gupta, Burak Tekin, Loren Herrera Hernandez
Journal: Journal of Clinical Oncology (2024)

TPS5108 Background: Penile cancer is a devastating malignancy that affects just over 2000 patients per year in the United States and approximately 40,000 worldwide. Metastatic or unresectable penile cancer is rapidly fatal in most cases and there are few effective systemic therapy options. 1 There is an urgent need for alternatives to chemotherapy such as immunotherapy or targeted therapy. Enfortumab vedotin (EV) is an antibody-drug conjugate targeting nectin-4 protein on the tumor cell surface and having efficacy in treatment of metastatic urothelial carcinoma. 2 Recent studies have demonstrated frequent and strong expression of nectin-4 in penile squamous cell carcinoma (PSCC). 3,4 In this setting, Mayo Clinic is leading a phase II trial of EV for advanced PSCC, currently in progress. Methods: This single arm, open-label, two-stage, phase II trial evaluates best overall response rate (BRR) to EV in patients with PSCC regional lymph node involvement or distant metastatic (M1) disease. Participants may have had any prior systemic therapy or be treatment naïve. Previously untreated patients must be ineligible for or have refused surgery or radiotherapy, have N2-N3 disease and are ineligible for or have refused neoadjuvant chemotherapy, or have clinical evidence of M1 disease. Participants will receive treatment with EV until disease progression, withdrawal, death, or limiting toxicity. Participants will receive EV 1.25 mg/kg intravenous on days 1, 8, and 15 of a 28-day cycle, with tumor assessment performed at 8-week intervals. The primary endpoint is the combined BRR of partial and complete responses (whether confirmed or unconfirmed) according to RECIST 1.1. Secondary endpoints are confirmed response rate, duration of response, progression-free survival, overall survival, adverse events, and BRR in HPV related and unrelated subgroups. Stage 1 will consist of 15 participants, and if there are 2 or more responses will proceed to Stage 2 with an additional 10 participants. The trial opened to enrollment in December 2023, and is active at Mayo Clinic sites in Minnesota, Arizona, and Florida. Clinical trial information: Funding and drug supplied by Astellas Pharma Global Development, Inc./Seagen Inc. NCT06104618. 1. Chahoud J, et al., Curr Opin Urol. 2022 Jan 1;32(1):8-16. 2. Powles T, et al. N Engl J Med. 2021 Mar 25;384(12):1125-1135. 3. Tekin B, et al. Hum Pathol. 2023 Dec;142:42-50. 4. Grass GD, et al. Eur Urol Open Sci. 2023 Jan 10;49:1-5. Clinical trial information: NCT06104618 .
Survival associated with chemotherapy and prognostic biomarkers in penile cancer at a reference hospital in the Northeast Brazil from 2000 to 2021.
Authors: Joao Paulo Holanda Soares, Maria do Perpétuo Socorro Saldanha Cunha, Carlos Gustavo Hirth, Paulo Goberlânio de Barros Silva
Journal: Journal of Clinical Oncology (2024)

5043 Background: Penile cancer is a rare neoplasm worldwide. Despite a higher incidence in the Brazilian Northeast region, data regarding chemotherapy (CHT) treatment of penile cancer in Brazil is scarce. The relationship between markers of immunosuppression in the tumor microenvironment of penile cancer and MDSCs (Myeloid Derived Suppressor Cells) is still poorly understood. Methods: 294 patients affected by Squamous Penile Cancer treated at the Haroldo Juaçaba Hospital (Ceará-Brazil) between 2000 and 2021 (82 underwent chemotherapy: 27 adjuvant, 31 neoadjuvant and 24 palliative ) were retrospectively evaluated due to their clinical and histopathological characteristics and the following immunohistochemical markers: PD-L1, CD8t (intratumoral), CD163t (intratumoral), CD84, HLA-DR II. We sought to correlate these biomarkers to clinical staging, type (neoadjuvant, adjuvant or palliative) and response to CHT, PFS post-Chemotherapy (PFS-CHT), Overall Survival by stage (OS) and OS post-Chemotherapy (OS-CHT). Results: The median age for all patients was 62,9 years (18-103). Partial penile amputation was the most common surgery (74%), followed by inguinal lymphadenectomy (56%). Platinum Doublet was administered in 95% of cases. OS at 5 years for stages I, II, III e IV was 95,3%, 93,6%, 87,4% and 14,8%, respectively. The response rate (RECIST) (PR, SD and PD) in those who underwent Neoadjuvant CT was 29% 22% and 48%, while in the Palliative group was 5%, 11% and 82% respectively. Median OS-CHT was 49 months in the adjuvant, 21 months in neoadjuvant and 12 months in palliative group (p&lt;0.001 adjuvant vs neoadjuvant/palliative); PFS-CHT was 11 months, 4 months and 1 month in the adjuvant, neoadjuvant and palliative group, respectively (p&lt;0.001). In the neoadjuvant group, those who underwent surgery (70%) had a PFS-CHT of 6 months versus 2 months in those who were not operated (p&lt;0.001). In univariate analysis, PFS-CHT was significantly higher in those who had lower expression of CD8t (9 vs 5 months; p=0.02), or CD163t (7 vs 5 months; p=0.043) or CD84 (7 vs 5 months; p =0.043). Conclusions: This is the largest retrospective study on chemotherapy and survival outcomes in Brazil. Patients who underwent surgery and adjuvant CHT had the best prognosis in terms of survival followed by those operated after neoadjuvant CHT. Lower expression CD163t, or CD84 (marker of MDSCs) or CD8t correlated with greater PFS-CHT. These data may help to understand the suppressive microenvironment in penile cancer and response to chemotherapy.