tbuckley/cabot-search huggingface dataset:
ARAMON: A phase 2, randomized, open-label study comparing darolutamide (DARO) vs enzalutamide (ENZA) monotherapy on serum testosterone levels in patients (pts) with castration-sensitive prostate cancer (CSPC) after biochemical recurrence (BCR).
Authors: Andrew Leonard Laccetti, Matthew Raymond Smith, Howard I. Scher, Frank Verholen, Patrick Adorjan, Manjari Dissanayake, Xin Gao
Journal: Journal of Clinical Oncology (2024)

TPS243 Background: DARO, a structurally distinct and highly potent androgen receptor inhibitor, has low blood–brain barrier (BBB) penetration and limited potential for drug–drug interactions. In phase 3 trials, DARO showed significant efficacy and a favorable safety profile. In ARAMIS (NCT02200614), DARO and androgen-deprivation therapy (ADT) significantly improved metastasis-free survival and overall survival (OS) vs placebo + ADT in pts with nonmetastatic castration-resistant prostate cancer. In ARASENS (NCT02799602), DARO + ADT + docetaxel significantly improved OS in pts with metastatic hormone-sensitive prostate cancer vs placebo + ADT + docetaxel. In both studies, the incidence of adverse events (AEs) was similar between treatment groups. Currently, the ARASTEP study (NCT05794906) is evaluating DARO and ADT in pts with high-risk BCR following primary therapy who have prostate-specific membrane antigen PET/CT-positive lesions. Based on a neuroimaging study of healthy volunteers, cerebral blood flow was not altered with DARO but was significantly reduced in brain areas related to cognition with ENZA. It is postulated that the low BBB penetration of DARO may result in lower serum testosterone elevations than those seen with ENZA, which may reduce the frequency of AEs. The ARAMON study (NCT05526248) will compare the effect of DARO and ENZA monotherapy on post-treatment testosterone levels in pts with CSPC who developed a BCR after definitive treatment for localized disease. Methods: ARAMON is a two-stage, open-label, phase 2 study of pts with histologically or cytologically confirmed adenocarcinoma of the prostate who experienced BCR after radical primary prostatectomy (RP) or radiation therapy (RT), with &lt;5 asymptomatic oligometastatic disease sites. Key inclusion criteria are prostate-specific antigen (PSA) ≥2 ng/mL, PSA doubling time of ≤20 months, serum testosterone &gt;150 ng/dL, and Eastern Cooperative Oncology Group performance status 0/1. During the lead-in phase, 25 pts will receive DARO 600 mg twice daily for 52 weeks. If serum testosterone criteria are met at 12 weeks, the study will proceed to the randomized phase where approximately 40 pts will be randomized 1:1 to DARO (600 mg twice daily) or ENZA (160 mg once daily) for 52 weeks. The primary endpoint is the change in serum testosterone level from baseline to Week 12. Secondary endpoints include the change in serum testosterone levels from baseline to Weeks 24 and 52; PSA at Weeks 4, 12, 24, 36, and 52; changes in blood levels of endocrine, glycemic, and lipid metabolism markers; incidence of AEs; and quality of life. As of September 2023, 23 of 25 planned pts in the lead-in phase have been enrolled. Clinical trial information: NCT05526248 .
Strategic treatment pause of first-line immune checkpoint inhibitor + VEGFR-tyrosine kinase inhibitor in patients with good or intermediate risk metastatic renal cell carcinoma (mRCC) in response at 1 year of treatment (SPICI-GETUG R05): A non-inferiority randomized clinical trial.
Authors: Marine Gross-Goupil, Felix Lefort, Mathieu Larroquette, Julien Asselineau, Eric Frison, Laurence Albiges, Alain Ravaud
Journal: Journal of Clinical Oncology (2024)

TPS487 Background: Treatment of mRCC consists of combination of either Immune Checkpoint Inhibitor (ICI)-Tyrosine Kinase Inhibitor (TKI) for all IMDC prognosis group, or ICI-ICI for intermediate and unfavorable IMDC groups. Treatments are maintained until disease progression or toxicity for a total duration of 2 years for ICI, in routine. Acceptability and feasibility of treatment pause of the TKI, with no detrimental effect on efficacy were reported in the prospective STAR trial. The good-risk population is characterized by prolonged survival, close to that reported in the intermediate risk population group with a single adverse prognostic factor. Therefore, a pause of ICI-TKI could improve quality of life, safety, and total cost of care without detrimental impact on oncologic outcomes. Methods: This non-inferiority, randomized, open-label, multicenter, parallel-group trial (NCT05219318) aims to compare treatment pause versus treatment continuation in good or intermediate risk mRCC patients with only one prognostic factor and a confirmed objective response (complete or partial) at 12 months of treatment with ICI-TKI. 372 patients (186 in France) will be recruited in tertiary hospitals and randomized in a 1:1 ratio with stratification by center, prognostic group (good/intermediate) and response (complete/partial). The primary objective is to test the non-inferiority of treatment pause versus continuation, with the estimation of the difference in 12-month progression rate after randomization, and its one-sided 97.5% confidence interval. The non-inferiority margin is set at 15%. An interim safety data monitoring at 6 months after randomization of the first third of participants (i.e. 60 per arm) will check progression rate after treatment pause. A formal interim futility analysis will be performed when 50% of the study sample reaches the primary outcome time point, using a Bayesian predictive power stopping rule and a futility threshold set at 20%. Secondary objectives are overall safety and tolerability, health-related quality of life, anxiety and depression, quality-adjusted survival, 2-year overall and progression-free survival. Others objectives include progression patterns (site, known lesions, or/and new lesions), subsequent treatment (type, efficacy), in the experimental arm. In France, healthcare resource utilization and costs at 12 months will be compared. The first participant was randomized in January 2023. 27 centers in France were selected and are gradually/progressively opening. The opening of European centers is being planned. Health Ministry and National Cancer Institute Funds. Clinical trial information: NCT05219318 .
LORIKEET: A phase 2, randomized, open-label study of lorigerlimab plus docetaxel versus docetaxel alone in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Sumit Kumar Subudhi, Ralph J. Hauke, Justin A Call, Jichao Sun, Denise Casey, Xiao X. Wei
Journal: Journal of Clinical Oncology (2024)

TPS242 Background: Lorigerlimab is an investigational bispecific, Fc-bearing (IgG4) DART molecule that binds PD-1 and CTLA-4. Lorigerlimab is engineered to enhance CTLA-4 binding in the tumor microenvironment (TME) while minimizing off-tumor CTLA-4 binding in normal tissue. 2 A phase 1 study of lorigerlimab monotherapy in 162 patients with advanced solid tumors (NCT03761017) demonstrated a manageable safety profile. The objective response rate (ORR) among 35 patients with heavily pretreated mCRPC and measurable disease was 25.7%. 1 Chemoimmunotherapy combination regimens have demonstrated improved outcomes over chemotherapy or immune checkpoint inhibitors given alone in multiple cancers. Although recent data showed lack of survival improvement when anti-PD-1 antibody was combined with docetaxel in mCRPC, 3 dual blockade of PD-1 and CTLA-4 with lorigerlimab may be an effective strategy to potentiate host immune responses in the TME with limited CTLA-4-associated toxicities. In addition to direct antitumor activity, docetaxel may stimulate antitumor immunity and enhance the immunomodulating effects of lorigerlimab. The phase 2 LORIKEET study will compare the combination of lorigerlimab plus docetaxel versus docetaxel alone in patients with mCRPC. Methods: Approximately 150 patients will be randomized 2:1 to lorigerlimab (6mg/kg Q3W) combined with docetaxel (75 mg/m2 Q3W) and prednisone (5mg BID) versus docetaxel and prednisone alone. Patients are stratified by the presence of visceral disease (yes vs no) and geographic region (North America vs other). Key eligibility criteria include age ³ 18; ECOG performance status 0 or 1; disease progression by PCWG3 criteria following prior androgen receptor axis-targeted therapy (e.g., abiraterone, enzalutamide, apalutamide); no prior taxane chemotherapy for mCRPC;immune checkpoint inhibitors. The primary endpoint is radiographic progression free survival (rPFS) per PCWG3 criteria. Secondary endpoints include ORR, duration of response, PSA response, safety, overall survival, and HRQOL measures including change in pain severity and time to first symptomatic skeletal events. Eligible patients randomized to receive docetaxel and prednisone alone who experience radiographic progression may remain on study and receive lorigerlimab monotherapy. Enrollment is ongoing. 1. Luke, ASCO-GU 2023, Abstract 155. 2. Berezhnoy, PMID 33377134. 3. Petrylak, ASCO-GU 2023, Abstract 19. Clinical trial information: NCT05848011 .
Men with adrenal-permissive <i>HSD3B1</i> genotype and prostate cancer mortality: Results from the Veterans Affairs Health System Million Veteran Program.
Authors: Rana R. McKay, Tyler J. Nelson, Meghana Pagadala, Craig Teerlink, Anthony Gao, Alex Bryant, Fatai Agiri, Kripa Guram, Kathryn Pridgen, Tyler M Seibert, Kyung Min Lee, Hannah Carter, Julie Ann Lynch, Richard Hauger, Brent S. Rose
Journal: Journal of Clinical Oncology (2024)

207 Background: The 3β-HSD1 protein, encoded by the HSD3B1 gene, catalyzes the rate-limiting step necessary of non-testicular testosterone and dihydrotestosterone production. The common adrenal-permissive HSD3B1(1245C) allele is responsible for encoding 3β-HSD1 protein with decreased susceptibility to degradation resulting in increased of extragonadal androgen synthesis. Retrospective studies have suggested an association with the HSD3B1 CC genotype and resistance in prostate cancer. Methods: We conducted a cohort analysis of patients with a diagnosis of prostate cancer enrolled in the Million Veteran Program with genotyping and phenotyping information available through Veterans Health Administration. The primary endpoint was to evaluate prostate cancer-specific mortality (PCSM) in the overall cohort. PCSM was defined as the time from diagnosis to death from prostate cancer, censored at the date of last VA follow-up. Secondary endpoints included incidence of metastases and PCSM in predefined subgroups. HSD3B1 genotype status was categorized as AA (wild type), AC (heterozygous), CC (homozygous). Results: The study included 5287 men with prostate cancer; 402 (7.6%) HSD3B1 CC, 1970 (37.3%) HSD3B1 AC, and 2915 (55.1%) HSD3B1 AA. The cohort included 29.6% (n=1567) Black men of whom 1.2% (n=19) were HSD3B1 CC. Cumulative incidence of PCSM at five years after prostate cancer diagnosis was higher among men homozygote for HSD3B1 variant genotype CC compared to heterozygotes AC and wild-type homozygotes AA (1.9% for AA vs. 2.1% for AC vs. 4.0% for CC, p&lt;0.017). While the cumulative incidence of metastases was similar in between HSD3B1 genotype groups (12.3% for AA, 11.8% for AC, 13.2% for CC, p=0.789), in patients who developed metastatic disease (n=619), the cumulative incidence of PCSM at five years was higher in the HSD3B1 CC group compared to AC and CC (19.2% for AA vs. 17.6% for AC vs. 37.3% for CC, p&lt;0.005). Conclusions: Among men with prostate cancer, HSD3B1 CC genotype is associated with inferior outcomes. The HSD3B1 biomarker may help identify patients who may benefit from therapeutic targeting of 3β-HSD1 and the androgen-signaling axis.
Monocyte to lymphocyte ratios and cancer-specific mortality for patients with renal cell carcinoma and inferior vena cava tumor thrombus.
Authors: Maxwell Sandberg, Rory Ritts, Mary Namugosa, Davis Temple, Wyatt Whitman, Claudia Marie Costa, Justin Refugia, Benjamin Eilender, Reza Mehrazin, Rafael Ribiero Zanotti, Patricio Garcia Marchiñena, Stenio Cassio Zequi, Alejandro Rodriguez
Journal: Journal of Clinical Oncology (2024)

444 Background: Renal cell carcinoma (RCC) with inferior vena cava (IVC) tumor thrombus carries a poor prognosis and presents complex medical management to urologists. Long-term data examining RCC with IVC tumor thrombus is sparse. Specifically, markers predicting cancer-specific survival are lacking. Recently, immune cell markers in cancer, such as neutrophils, lymphocytes, and monocytes, have come into focus. These cell counts and/or ratios may provide a window into cancer-specific outcomes. The purpose of this study was to examine the use of immune cell ratios in patients with RCC and IVC tumor thrombus to predict survival outcomes through a collaboration project across North and South America. Methods: Patients were included in this study if they had a diagnosis of RCC with IVC tumor thrombus and underwent nephrectomy with IVC thrombectomy for their RCC. Data was reviewed and entered into a multi-institutional/continental database. Complete blood counts taken as close to the date prior to/date of surgery were used to calculate immune cell ratios. Neutrophil to (/) lymphocyte ratios were done by dividing patients’ neutrophil cell count by their lymphocyte count. Monocyte/lymphocyte ratios were calculated in the same manner. Independent samples t-test was used to test for significance in cause of death post-operatively (RCC versus non-RCC cause) based on immune cell ratio. Results: There were 107 patients included in the study with long-term follow-up data (Mean: 2.6 years; Range: 0-16-years). Of all patients, 43/107 died by the end of the study, with 31/43 (72.1%) dying due to RCC and 12/43 (27.9%) from other causes. No difference existed in neutrophil/lymphocyte ratios based on cause of death (p=0.260). Monocyte/lymphocyte ratios were significantly lower in those who died from RCC relative to another cause (p=0.035). Conclusions: Immune cell ratios may have a role in predicting death from RCC. In our study, monocyte/lymphocyte ratios were significantly lower in patients who died from RCC compared to death from other reasons. Our results stem from a multi-continental/institutional study, and thus hold clinical utility as an increased focus is turned towards including diverse populations in research. Urologists may consider monocyte/lymphocyte ratios in the future when managing patients with RCC and an IVC thrombus. [Table: see text]
Neoadjuvant pamiparib plus abiraterone and ADT for high-risk/very high-risk localized prostate cancer: Results of a prospective study.
Authors: Junlong Zhuang, Shun Zhang, Xuefeng Qiu, Feng Zhou, Hongqian Guo
Journal: Journal of Clinical Oncology (2024)

327 Background: Androgen receptor (AR) signaling inhibition increases genomic instability of double-stranded DNA breaks, and co-inhibition of AR and PARP induces synthetic lethality in multiple preclinical models. In this study we tested the efficacy and safety of neoadjuvant pamiparib plus abiraterone and ADT in HRLPC/VHRLPC before radical prostatectomy (RP). Methods: In this phase II single-arm neoadjuvant trial, patients with HRLPC/VHRLPC (defined as Gleason ≥ 8 and/or cT3-4N0-1 and/or PSA≥ 20 ng/mL) were enrolled to evaluate the safety and antitumor efficacy of pamiparib before prostatectomy. Patients received pamiparib plus abiraterone and ADT for 4 months followed by prostatectomy. The primary objective was the rate of pathological complete response (pCR) or minimal residual disease (MRD). MRD was defined as ≤0.5cm of tumor or residual cancer burden ≤0.25 cm3 (RCB = tumor volume x cellularity). Secondary endpoints include PSA response, surgical staging at RP, the rate of PSA recurrence 12 months after surgery, and safety. Results: A total of 30 pts were enrolled, 29 pts (HRRm n=7) completed the full course of study treatment and underwent RP. One patient declined surgery for personal reasons and received further systemic therapy. The median age was 66 (range 41-77). Clinical characteristics were typical of high-risk disease: median PSA 34.4 ng/ml (range 10.8-204) and clinical stage cT3 (n=27), Gleason 8-10 (n=20),9 pts had enlarged pelvic lymph nodes. Following 4 months of therapy, the median pre-RP PSA was 0.103 ng/ml (range 0.006 -1.1). Final pathologic results showed that 8 pts (27.5%) achieved pCR or MRD, 3 pts (10.3%) achieved pCR, 5 patients (17.2%) achieved MRD, and 18 patients (62%) had staging downgrades, with no patients experiencing progression. Compared to patients with an HRR wild type (HRRwt), those with HRR mutations had no difference in pCR or MRD. The margin positivity rate was 6.8%(n=2) in 29 pts, all of whom were T3 stage patients. No Grade 3/4 drug-related adverse event was observed. The most common 1-2 adverse event were anaemia (48.2%), AST/ALT increased (34.4%) and hypertriglyceridemia (44.8%). Conclusions: Neoadjuvant therapy of pamiparib plus abiraterone and ADT for 4 months was effective and safe in pts with HRLPC/VHRLPC. Clinical trial information: NCT05376722 .
Describing the genomic landscape of bladder cancer histologic subtypes.
Authors: Rafee Talukder, Rachel Berg, Minxuan Huang, Vanessa M. Nepomucino, Melissa Conrad Stoppler, Dimitrios Makrakis, Aihua Edward Yen, Martha P. Mims, Seth P. Lerner, Solomon L. Woldu, Yair Lotan, Evan Y. Yu, Ali Raza Khaki, Jeanny B. Aragon-Ching, Petros Grivas
Journal: Journal of Clinical Oncology (2024)

680 Background: Histologic subtypes of bladder cancer are associated with poor prognosis and therapy resistance; understanding of their biology can help identify therapies to improve outcomes. We aimed to describe the genomic alteration (GA) landscape of pure urothelial (UC) and histologic subtypes: plasmacytoid (PC), micropapillary (MP), sarcomatoid (SA), small cell/neuroendocrine (SC), squamous cell differentiation (SQ), adenocarcinoma (AD). Methods: Approximately 2165 patients (pts) were selected from the Tempus multimodal database. Selection criteria included diagnosis of bladder cancer (UC or histologic subtypes: PC, MP, SA, SC, SQ, AD) and sequencing via the Tempus xT assay. Genomic and immunotherapy biomarkers, including mutations, fusions, copy number variants, tumor mutation burden (TMB-high defined as ≥10 mutations/Mb) and MSI status were determined for each subtype and compared using Fisher’s Exact and Kruskal-Wallis tests. Results: Among 2165 identified pts, 1738 (80%) had UC (84% pure and 16% mixed histology), Table shows genomic alterations per histologic subtype. Median age at diagnosis was 70. The overall cohort included male (73%), white (84%), and ever smokers (71%). Of 1197 pts with staging information available, 71% tumors were stage IV. TMB-H and MSI-high status were noted in 17% and 1.1% of the overall cohort, respectively, and were relatively similar across histologies. PD-L1 positive status by IHC was noted in 30% in the overall cohort, and statistically lower in PC (7.7%), SC (10%) and AD (8.8%) vs UC (32%), SA (46%) and SQ (45%) (p&lt;0.001). Compared to UC, FGFR3 was significantly lower in SC (9% vs 1%, p=0.003) and AD (9% vs 1%, p=0.001). We noted FGFR2/3 fusions in 2.6% of the entire cohort and all cases were UC. Compared to UC, ERBB2 was significantly higher in MP (13% vs 45%, p&lt;0.001) and lower in SQ (13% vs 2%, p&lt;0.001). ERBB2 amplification was more common in MP (16%) vs 8% in PC, 6.2% in UC, and 1.6% in SC. Conclusions: Distinct genomic alteration patterns were found among different histologic subtypes of bladder cancer and conventional UC. Assessing the genomic landscape of bladder cancer can help identify potential ‘actionable’ targets and biomarkers, and better inform clinical trial designs. Limitations include lack of clinical data annotation, tumor heterogeneity and retrospective study nature. [Table: see text]
Preclinical characterization of human Kallikrein 2 (hK2) as a novel target for the treatment of prostate cancer.
Authors: Fei Shen, William Kevin Kelly, Neeta Pandit-Taskar, Theresa McDevitt, Ryan Smith, Krista Menard, Kathryn Packman, Ruchi Chaudhary, Brent Rupnow, Margaret K. Yu, Mary E. Guckert, Shaozhou Ken Tian, Gerald Chu, Hong Xie, Daniel Patricia, Steven I Max, Michael J. Morris
Journal: Journal of Clinical Oncology (2024)

202 Background: Treatment options that are durably effective for patients with metastatic (m) castration-resistant prostate cancer (CRPC) remain limited despite available therapies, highlighting a continued unmet need for novel drug development. hK2 is overexpressed in prostate cancer (PC) and has little to no expression in non-prostate tissues. Here, we use a series of preclinical experiments to evaluate hK2 as a therapeutic target in PC. Methods: hK2 expression was assessed by immunohistochemistry (IHC) in non-metastatic (nm) castration sensitive PC (CSPC; n = 100), mCSPC (n = 98), and mCRPC (n = 45) samples obtained from tumor banks and warm autopsy tumor microarrays. Multiplex immunofluorescence (IF) was used to assess hK2 expression at different mCRPC tumor sites. hK2 cell surface expression in a human prostate cancer cell model (VCaP) and fresh mCRPC patient tumor samples was assessed by flow cytometry. hK2-targeting antibody internalization over time was visualized by confocal IF microscopy in VCaP cells. VCaP xenograft models in immune-compromised NSG mice were used to evaluate anti-tumor activity, defined as change in percent of tumor growth inhibition (ΔTGI), following treatment with 3 unique hK2-targeting experimental agents (Table). Whole-body planar and SPECT/CT imaging were used to assess hK2-targeting antibody tumor uptake in patients with mCRPC. Results: IHC confirmed robust hK2 expression across different PC stages with homogenous expression in nm/mCSPC and increased heterogeneity in mCRPC. Mean percent tumor staining of hK2 in mCRPC samples was 67.6% (bone), 65.7% (lymph nodes), and 33.5% (liver) by multiplex IF. Correlation of hK2 expression across mCRPC bony lesions (r = 0.74, p &lt; 1.6e -06 ) was observed, suggesting intrapatient and interlesion homogeneity. Confocal microscopy demonstrated hK2 cell surface expression in VCaP cells, with rapid antibody internalization within 3 hours. Flow cytometry confirmed hK2 cell surface expression in both VCaP cells and mCRPC samples. Robust antitumor activity was observed following treatment with each hK2-targeting agent in the xenograft mouse model (Table). Whole-body and SPECT/CT scans confirmed accumulation of the hK2-targeting antibody to PC tumors in patients with mCRPC. Conclusions: hK2 expression was homogenous in nm/mCSPC, with increased heterogeneity in mCRPC. Antitumor activity was observed across hK2-targeting agents. These data demonstrate that therapeutic strategies targeting hK2 hold promise in PC treatment and support further investigation of these agents in clinical studies. [Table: see text]