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Metabolic determinants of exceptional response to immune checkpoint inhibition in renal cell carcinoma.
571 Background: Immune checkpoint inhibitors (ICI) have led to remarkable, long-lasting responses in a subset of patients with metastatic renal cell carcinoma (RCC). However, the molecular mechanisms driving these exceptional responses (ER) are not fully characterized. We previously observed that a high tertiary lymphoid structure (TLS) signature is associated with ER. Here, we explore metabolic molecular determinants that may influence ER in patients treated with ICI and VEGF inhibitors. Methods: We analyzed genomic and transcriptomic data from 357 treatment-naïve patients with advanced clear cell RCC who were given PD1/L1 and VEGF inhibitors (ICI/VEGFi) in a phase III clinical trial. Patients were categorized into three groups: (a) extreme responders (ER), including those with complete response (CR) and progression-free survival (PFS) of at least 12 months, or partial response (PR) with significant tumor shrinkage and prolonged PFS; (b) intermediate responders (IR), patients with CR or PR not meeting ER criteria; and (c) patients with progressive disease (PD). Whole exome sequencing (WES) was used to analyze somatic mutations, copy number changes, and compute clonal neoantigen load (CNL). Gene set enrichment analysis (GSEA) was performed to explore molecular pathways, and multivariate Cox proportional hazards analysis identified PFS predictors. Results: Metabolic pathway enrichment was notable in ER patients with low TLS signatures, with pathways such as peroxisome function, xenobiotic and bile acid metabolism, adipogenesis, fatty acid metabolism, and oxidative phosphorylation showing upregulation. These findings held after adjusting for tumor purity. Next, we defined a metabolic gene signature based on the enriched metabolic genes in TLS-low ER samples compared to TLS-high ER samples. ER patients with low TLS scores had significantly higher metabolic signature scores than IR (p=0.00062) and PD (p=0.00012) patients. Higher metabolic signature scores correlated with improved PFS (p=0.054) and overall survival (OS) (p=0.0037). Multivariable analysis confirmed that favorable IMDC risk (p<0.001) and a high metabolic signature (p=0.01) were independent predictors of ER. Conclusions: Metabolic pathways are critical drivers of exceptional responses to ICI in RCC, especially in patients with low TLS scores. A high metabolic gene signature may serve as a predictive biomarker for ER, offering insights into new therapeutic strategies targeting metabolic reprogramming in this unique subset of patients.
OMAHA-003: A phase 3 study of CYP11A1 inhibitor opevesostat versus next-generation hormonal agent (NHA) switch in metastatic castration-resistant prostate cancer (mCRPC) after NHA and taxane-based chemotherapy.
TPS286 Background: The androgen receptor (AR) plays a pivotal role in prostate cancer pathogenesis, even after progression on androgen-directed therapies (ADT). In patients with mCRPC, activation of AR ligand binding domain (AR-LBD) somatic point mutations is a common mechanism of resistance to ADTs. Opevesostat (MK-5684; ODM-208) is an oral, nonsteroidal inhibitor of cytochrome P450 11A1 (CYP11A1), which catalyzes the first and rate-limiting step of steroid biosynthesis. By inhibiting CYP11A1, opevesostat suppresses the production of all steroid hormones and their precursors that may promiscuously activate the AR signaling pathway. Opevesostat showed antitumor activity in patients with heavily pretreated mCRPC, and in those with AR-LBD mutations, in the phase 1/2 CYPIDES trial (Fizazi et al. NEJM Evid. 2024). The randomized, open-label, phase 3 OMAHA-003 study (NCT06136624) is evaluating the efficacy and safety of opevesostat versus NHA switch in patients with mCRPC who received NHA and taxane-based chemotherapy. Methods: Eligible patients havemCRPC (unselected for AR-LBD mutations) that progressed on ADT ≤6 months of screening and during/after treatment with 1 NHA or 1-2 taxane-based chemotherapies. Approximately 1200 patients (300 with, 900 without AR-LBD mutations) will be randomly assigned 1:1 to opevesostat 5 mg PO BID (+ dexamethasone 1.5 mg and fludrocortisone 0.1 mg QD) or enzalutamide 160 mg PO QD (if prior abiraterone) or abiraterone acetate 1000 mg PO QD (if prior enzalutamide/darolutamide/apalutamide). Primary endpoints are radiographic progression-free survival per Prostate Cancer Working Group 3 (PCWG3)-modified RECIST v1.1 by blinded independent central review (BICR) and overall survival in patients with AR-LBD mutation-positive and -negative disease, separately. Secondary endpoints include time to initiation of first subsequent anticancer therapy or death; objective response rate and duration of response per PCWG3-modified RECIST v1.1 by BICR; and safety. Enrollment is ongoing. Clinical trial information: NCT06136624 .
Frequency and impact of a genome-wide homologous recombination deficiency signature (HRDsig+) on the genomic landscape of clinically advanced urothelial bladder carcinoma (CAUBC).
845 Background: CAUBC (metastatic and surgically incurable advanced UBC) is a challenging with significant need for improvement in systemic therapies. We aimed to explore HRD sig status and related biomarkers, including other GA, to generate hypothesis and inform clinical trial designs for these patients. Methods: 8825 cases of CAUBC underwent comprehensive genomic profiling (CGP) to examine all classes of genomic alterations (GA). MSI high status, tumor mutation burden (TMB) levels, genomic ancestry and trinucleotide mutational signatures were determined from the sequencing data. HRDsig status was calculated using a broad set of genome-wide copy number features. PD-L1 was determined by IHC using the Dako 22C3 tumor proportional score (TPS) system. Results were compared using the Fisher exact system with the Benjamini-Hochberg adjustment to correct for false discovery. Results: 387 (4.4%) of CAUBC cases featured a positive HRDsig status (HRDsig+). The median age (62-63) was similar in the HRDsig+ and HRDsig- groups and both groups were predominantly male (75-77%). The GA/tumor frequencies were similar (5-6). MSI-high status was extremely low in both groups (0.8% vs 0%). The median TMB (10 vs 6.3; P<.0001) and frequency of TMB > 10 mutations/Mb (50.9% vs 34.8%; P=0.016) was higher in the HRDsig+. Trinucleotide mutational signature distribution, PD-L1 low (1-49% TPS) and PD-L1 high (≥50% TPS) expression were similar in both groups. As anticipated, GA in genes associated with HRD including BRCA1 (9.0% vs 1.6%; P<0.0001), BRCA2 (17.1% vs 2.5%; P<0.0001), ATM (9.6% vs 5.3%; P=0.0003) and RAD21 (8.5% vs 3.4%; P<0.0001) were more frequent in the HRDsig+ cases. In the HRDsig- group, 83.7%/87.0% of BRCA1 / BRCA2 mutated CAUBC were mono-allelic, likely non-driver GA, respectively. FGFR3 GA were significantly more frequent in the HRDsig- CAUBC (18.1% vs 10.9%; P=0.001). GA in ERBB2 (17.8-18.5%) and ERBB3 (6.2-7.8%) were similar in both groups. MTOR pathway related mutations, including PTEN (4.5-6.2%) and PIK3CA (18.6-21.7%) were similar in both groups. GA in TERT were more frequent in the HRDsig- group (78.9% vs 57.6%; P<0.0001) and GA in TP53 were more frequent in the HRDsig+ cases (72.1% vs 60.5%; P<0.0001). Conclusions: With a 4.4% frequency, HRDsig+ status is a relatively uncommon biomarker in CAUBC. This finding may inform clinical trial designs, for example with PARP inhibitors and other ‘HRD-targeting’ agents. Limitations include the retrospective nature, potential selection bias and lack of clinical outcomes annotation. Genomic differences between HRDsig- and HRDsig+ CAUBC groups. CAUBC HRDsig- CAUBC HRDsig+ P value EUR Ancestry 85.2% 78.6% 0.003 ATM 5.3% 9.6% 0.003 BRCA1 1.6% 9.0% <.0001 BRCA2 2.5% 17.1% <.0001 FGFR3 18.1% 10.9% 0.001 RAD21 3.4% 8.5% <.0001 TP53 60.5% 72.1% <.0001 RB1 2.7% 5.4% <.0001 TMB≥10 mut/Mb 34.8% 50.9% 0.016
CORE-008: A phase 2, multi-arm, multi-cohort, open-label study to evaluate intravesical cretostimogene grenadenorepvec in participants with high-risk non-muscle invasive bladder cancer.
TPS901 Background: Treatment for patients with High-Risk Non-Muscle Invasive Bladder Cancer (HR NMIBC) consists of Transurethral Resection of Bladder Tumor (TURBT) followed by intravesical Bacillus Calmette–Guérin (BCG). Despite high initial response rates, over 50% of patients will recur and 20-40% are at risk for progression. Treatment of HR NMIBC is challenged by the BCG shortage, thus there exists a need for clinically effective, well-tolerated, and readily available treatment options for patients with HR NMIBC. Cretostimogene grenadenorepvec is an oncolytic immunotherapy with a dual mechanism of action. It selectively replicates and lyses bladder cancer cells with Retinoblastoma (Rb)-E2F pathway alterations. The subsequent release of virus- and tumor- specific antigens initiate antitumor immune activation amplified by the GM-CSF transgene, a potent cytokine. Cretostimogene received both Fast Track and Breakthrough Therapy Designations by the US FDA for the BCG-Unresponsive HR NMIBC with CIS indication. Given the strength of these data, the CORE-008 clinical trial ( NCT06567743 ) was developed as a Phase 2, multi-arm, multi-cohort trial to further evaluate the safety and efficacy of cretostimogene in patients with HR NMIBC. Methods: Eligibility criteria include pathologic confirmation of HR NMIBC as defined by the American Urologic Association (AUA) Guidelines. Cohort A (BCG-naive) is comprised of CIS +/- HG Ta/T1 participants who have not received prior BCG. Cohort B (BCG-exposed) will consist of CIS +/- HG Ta/T1 or papillary-only patients who have received prior BCG, and recurred either immediately after induction therapy (BCG-resistant) or recurred at a delayed timepoint, after adequate or inadequate BCG. Intravesical cretostimogene will be instilled in combination with n-dodecyl-β-D-maltoside (DDM), an excipient, that enhances adenoviral delivery, for six weekly doses during the induction phase, followed by three weekly maintenance cycles quarterly through month 12, then every six months through month 36. Re-induction is permitted. The primary endpoint for the CIS population is Complete Response (CR) at any time. High-Grade Event-Free Survival is the primary endpoint for papillary-only participants. Secondary endpoints will include Duration of Response, all-cause Event-Free Survival, Bladder Cancer Specific Survival, Radical Cystectomy Free Survival, and safety. Exploratory outcome measures include Health-Related Quality of Life, Overall survival, and biomarker assessments. Additional HR NMIBC cohorts are under development. Multiple clinical sites have been identified and Cohort B has received collaborative support from the Society of Urologic Oncology-Clinical Trials Consortium. Clinical trial information: NCT06567743 .
Evaluating molecular alteration profiles to distinguish intraductal carcinoma of the prostate.
407 Background: Intraductal carcinoma of the prostate (IDC-P) is an intra-acinar and/or intraductal neoplastic epithelial proliferation that is a distinct entity in the 2016 WHO classification system for prostate cancer. Clinically, it is associated with higher grade tumors and a more aggressive disease course with a high risk of local recurrence and distant metastasis. However, the molecular underpinnings of IDC-P are not well elucidated. We present comprehensive molecular profiling data from the largest cohort of IDC-P cases reported to date, with direct comparison to a matched cohort of adenocarcinoma cases. Methods: We identified radical prostatectomy (RP) cases from Caris Life Sciences database, classified as prostatic adenocarcinoma with Grade Group 4-5 or had the words “cribriform”, “necrosis”, or “intraductal” in the pathology report, for which imaging files were available. Digitized H&E slides underwent central pathology review by a board-certified genitourinary pathologist (IW) to identify the presence of IDC-P according to the 2022 WHO classification. Cases with IDC-P were compared to cases without IDC-P on central review or lacked reference to “cribriform”, “necrosis”, or “intraductal” in the RP pathology report (non-IDC-P). Prostatic tumor specimens were sequenced at Caris Life Sciences via NextGen DNA Seq (592 gene panel or whole exome) and RNA Seq (whole transcriptome). Results: 4,880 cases were identified, of which 176 were confirmed to have IDC-P with median age of 63.5 years. 43% (76/176) of IDC-P cases were Grade Group 5 and 99% (175/176) were Grade Group 3 or higher. Compared to non-IDC-P cases, the IDC-P cohort had significantly more mutations in MUTYH (4.5% vs. 1.4%, p <0.01), FANCA (2.7% vs. 0.5%, p <0.01), NBN (2.5% vs. 0.6%, p <0.05), and MTOR (0.6% vs. 0.1%, p <0.05), and fewer alterations in AR (0% vs. 0.7%, p <0.01) and AR-V7 splice variants (5.5% vs. 6.2%, p <0.001). IDC-P tumors were enriched for DLL3 and CEACAM5 expression with lower expression of STEAP1, TROP2, ERBB2, and B7-H3 compared to non-IDC-P. Patients with IDC-P had significantly higher neuroendocrine prostate cancer (NEPC) signature scores, with similar AR signature scores compared to non-IDC-P. The tumor microenvironment of IDC-P tumors had significantly higher cell fractions of M2 macrophages and regulatory T cells, and fewer dendritic cells. Conclusions: Our findings demonstrate that IDC-P possesses a distinct molecular profile and immunologic phenotype. Specifically, we observed an increased prevalence of DNA repair alterations, including in the MUTYH gene. Furthermore, IDC-P showed an increased NEPC signature and a more immunosuppressive phenotype. This information is important for developing personalized treatment strategies for histologically distinct prostate cancer subsets.
Assessment of the proficiency of ChatGPT-4o in an image-based robot-assisted radical prostatectomy scenario.
423 Background: Surgery is a process that heavily relies on complex visual information. Many AI-based surgical teaching and assistance applications have emerged. However, the application of the newly released ChatGPT-4o in surgical contexts remains unexplored. This study aims to investigate the ability of ChatGPT-4o in analyzing and recognizing anatomical structures, surgical procedures, and operational precautions based on image information in a surgical context. Utilizing screenshots from robot-assisted radical prostatectomy videos sourced from the internet. Methods: We developed a test comprising 77 images and 65 questions, with a total score of 100 points. The test includes sections on anatomical structures, surgical procedures, and operational precautions. We sequentially input the questions into the ChatGPT-4o model and employed strategies to enhance its performance during the test. A passing score was set at 60 points or above, and an excellent score at 80 points or above. Results: ChatGPT-4o achieved a score of 68, surpassing the passing threshold. The accuracy for non-image questions was higher than for image-based questions (85.71% vs. 58.46%, χ² = 7.78, p = 0.005), and questions with fewer images had a higher accuracy than those with multiple images (71.11% vs. 30.00%, p < 0.001). Furthermore, we found ChatGPT-4o performed differently in recognizing different structures, with the highest accuracy for questions involving muscle and fascia (100%) and the lowest for those involving nerve and vessel structures (33.33%). Conclusions: ChatGPT demonstrated commendable abilities in image recognition and problem analysis in surgical contexts. We hope that the results of this study will contribute to future applications of ChatGPT in AI-assisted surgical teaching and assistance.
Large language models (LLMs) for inferring genomic characteristics and facilitating genomic literacy in prostate cancer (PCa) patients.
261 Background: Clinicians use next-generation sequencing (NGS) to tailor targeted treatments for PCa patients. However, the results are often available in unstructured formats and are saturated with technical jargon, making them inaccessible for patients. Therefore, we aimed to assess the efficacy of LLMs to accurately extract genomic characteristics from unstructured reports and generate patient-friendly summaries for ease of variant interpretation in PCa patients. Methods: This retrospective study included patients with PCa who underwent NGS from 2023-2024. The GPT4 model was utilized using structured zero-shot prompts to extract genomic characteristics from unstructured reports in a non-decomposed manner. Prompt development was conducted iteratively using a 2% random sample of the dataset. Genomic characteristics ascertained by LLM were assessed against held out vendor-curated test dataset for evaluation. Performance was assessed using weighted evaluation metrics (precision, recall, and F1-score). Additionally, the extracted variables were organized using rule-based criterion and presented as a separate prompt to GPT4 to generate summaries for interpretation at the level of each biologically relevant variant. Mean Flesch-Kincaid scores and Vocd-D statistic with standard deviations were computed to assess readability and lexical diversity of LLM-generated variant interpretation summaries. Results: A total of 331 patients (370 NGS reports) were included in the study. Evaluation on the held-out test dataset (Table) showed that the weighted average precision ranged from 80% for extracting tumor mutational burden to 100% for extracting the CtDNA fraction from unstructured reports. The weighted average recall ranged from 85% for extracting CtDNA tumor fraction to 99% for ascertaining variant/alteration. The weighted average F1-scores varied from 0.83 for extracting tumor mutational burden to 1.0 for extracting specimen site from NGS reports. The mean Flesch-Kincaid score was 8.29 ± 1 indicating average/standard readability ease. The mean Vocd-D statistic was 7.55 ± 1 indicating focused summaries, however, with limited lexical diversity. Conclusions: This study suggests that large language models can effectively extract genomic characteristics from unstructured reports and can potentially improve genomic literacy among prostate cancer patients by providing easy-to-interpret variant summaries. However, targeted prompting may be required to increase lexical diversity for improved engagement. Performance across different genomic characteristics. Category Precision Recall F1-Score Altered gene 0.86 0.97 0.89 Variant/alteration type 0.98 0.99 0.98 Variant allele fraction 0.96 0.96 0.96 Test name/type 1 0.99 1 Specimen site 1 0.99 1 Tumor mutational burden 0.8 0.93 0.83 CtDNA tumor fraction 1 0.85 0.92 MSI status 0.99 0.97 0.98
VORSIN-RCC: Vorolanib plus sintilimab for advanced renal cell carcinoma after failure of prior immune checkpoint inhibitors-based combination therapy.
TPS616 Background: Despite substantial advances in therapy over the past 20 years, the median progression-free survival (mPFS) for advanced RCC patients treated with first-line tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) remains around 20 months (Motzer RJ et al., NEJM 2021, Choueiri TK et al., NEJM 2021). Moreover, subsequent treatments post-first-line progression exhibit inadequate efficacy. A phase Ib/II single-arm trial achieved a high objective response rate (ORR) with lenvatinib plus pembrolizumab in patients post-ICI progression (Lee CH et al., Lancet Oncol 2021). However, other trials showed that ICIs did not benefit advanced RCC patients who have progressed after receiving ICIs (Pal SK et al., Lancet 2023, Choueiri TK, et al., Lancet 2024). The failures of previous ICI re-challenges may be related to the limited efficacy of PD-L1 blockade (atezolizumab) in RCC and the reduced dosage of tivozanib, whose efficacy is closely related to its blood concentration. So we designed a trial to assess the efficacy and safety of the full-dose TKI vorolanib, with favorable safety profiles, combined with the PD-1 inhibitor sintilimab in advanced RCC patients who have failed prior immune combination therapy. Methods: VORSIN-RCC is a prospective, multicenter, single-arm, phase II study enrolling patients with pathologically confirmed RCC. It includes individuals with metastatic or stage IV disease (2017 AJCC 8th edition TNM staging system) who have progressed on prior targeted combination immunotherapy, dual checkpoint inhibitor therapy, or immune monotherapy. Based on historical data, the mPFS for advanced RCC patients previously treated with immune-based combination therapy is approximately 7.96 months for targeted therapy alone and 10.6 to 12.2 months for combined targeted and immunotherapy. Using these figures, with a reference mPFS (m 0 ) of 7.96 months and a desired mPFS (m 1 ) of 11.2 months, the sample size was calculated for a 24-month enrollment period and a total trial duration of 36 months. A one-sided significance level (α) of 0.05, power of 0.8018, dropout rate of 10%, and a Weibull distribution shape parameter (k) of 1 were used. The sample size was determined using PASS software with a one-sample log-rank test estimation method, resulting in an expected sample size of 67 patients for this study. Enrolled patients will receive oral vorolanib tablets (200 mg/day) combined with intravenous sintilimab (400 mg every 3 weeks). The primary endpoint is PFS. Secondary endpoints include ORR, overall survival (OS), adverse events (AEs), disease control rate (DCR), duration of response (DoR), patient quality of life (QoL), and pain score. Both ORR and DCR are assessed using RECIST 1.1 and imRECIST criteria. This study is actively recruiting. Research Sponsor: Hao Zeng. Clinical trial information: NCT06523049 .
Avelumab maintenance in patients with metastatic urothelial carcinoma in a real-life expanded-access program (EAP).
708 Background: This study evaluates the real-world efficacy and safety of avelumab maintenance therapy in metastatic urothelial carcinoma (mUC) patients who have not progressed following first-line platinum chemotherapy, using data from the EAP. Methods: The primary endpoint was the overall survival (OS), progression-free survival (PFS) and secondary endpoints included safety. PFS and OS were estimated by using the Kaplan-Meier method. Results: One hundred seventeen patients who received at least one cycle of Avelumab. The median number of first-line platinum-based chemotherapy cycles was 5 (range, 3-6). Patients’ characteristics were illustrated in Table 1. The median follow-up was 12.1 months. The 12-month OS rate was 78% (95% CI, 74.5%-79%), while the median OS was not reached. The 12-month PFS rate was 32% (95% CI, 29%-35%) and the median PFS was 5.3 months (95% 3.4–7.1). In univariate analysis, the median PFS were 2.9 vs 5.4 months in patients with or without liver metastases (p=0.001) and 2.8 vs 5.3 months, in patients with hemoglobin levels below or higher than 10 mg/dl(p=0.06), 8.8 vs 4.1 months in patients with lymph nodes only versus other site metastases(p=0.05), respectively. However, the median PFS were 5.6 vs 4.9 months in first-line cisplatin base chemotherapy versus carboplatin (p=0.7), 7.3 versus 4.9 months in 4≤ cycle chemotherapy versus 4 >cycle(p=0.4), and 5.7 versus 5.3 months in response to first line chemotherapy (CR vs PR and Stabil response) (p=0.4) were not statistically significant for PFS. Thirty-one percent of patients experienced a treatment-related adverse event of any grade, and 9 (7.6%) of patients had a grade 3–4 treatment-related adverse event. Conclusions: Avelumab demonstrated effectiveness and tolerability as a maintenance treatment for mUC patients who had not progressed following first-line platinum-based chemotherapy regardless of first line chemotherapy regimen, chemotherapy cycles and response to first line chemotherapy. Liver metastases, only lymph node metastases and hemoglobin level significant factors on PFS. Patient Characteristics (n=117) n % Age (median, years) : 66 (43-84) Male Sex 94 80.3 Site of Primary Tumor Bladder 93 79.5 Renal Pelvis 12 10.3 Ureter 10 8.5 Urethra 2 1.7 Histological Subtype Urothelial Carcinoma 112 95.7 Mixed Histology (urothelial+variant) 5 4.3 ECOG-PS 0 51 43.5 1 64 54.8 2 2 1.7 Baseline Creatinine Clearance <60 ml/min 48 41 Baseline Hemoglobin concentration <10 g/dl 18 15.4 Tobacco Use Current 16 13.7 Previous 70 59.8 Never 24 20.5 Unknown 7 6 Metastatic Site at Baseline Visceral 79 67.5 Liver 9 7.7 Lymph Node Only 42 35.9 Metastatic at the time of diagnosis 71 60.7 Neoadjuvant Chemotherapy 8 6.8 Cystectomy 60 51.3 Palliative/Curative Radiotherapy 13 11.1 Previous Chemotherapy Cisplatin-Gemcitabine 65 55.5 Carboplatin-Gemcitabine 47 40.2 ddMVAC 5 4.3
Circulating tumor cell RNA biomarker for bavdegalutamide (ARV-110) in metastatic castration-resistant prostate cancer without AR T878/H875 mutations.
235 Background: Bavdegalutamide (bavdeg; formerly ARV-110) is a first-in-class oral proteolysis targeting chimera (PROTAC) protein degrader that selectively targets androgen receptor (AR). A phase 1/2 study of bavdeg showed clinical activity in patients with metastatic castration-resistant prostate cancer (mCRPC) after 1-2 prior AR-targeted therapies, particularly in those harboring AR T878X/H875Y mutations. Although some patients with wildtype AR showed clinical benefit from bavdeg, no biomarker exists to select this subgroup of patients. Here we evaluated a circulating tumor cell (CTC) RNA biomarker for its potential to identify patients with mCRPC who may benefit from bavdeg in the phase 1/2 study despite the absence of AR T878X/H875Y mutations. Methods: Patients with mCRPC and disease progression after >1 prior novel hormonal agents were enrolled in the phase 1/2 study of bavdeg and consented for prospective collection of pre-treatment blood for CTC analysis at a single institution. CTCs were isolated using a negative selection microfluidic CTC enrichment device and analyzed for RNA expression of a panel of prostate cancer genes ( AGR2, FAT1, FOLH1, HOXB13, KLK2, KLK3, STEAP2, TMPRSS2, AR-V7 ) using a multiplex droplet digital PCR assay. A composite gene expression score (CTCm; Miyamoto et al. Cancer Discov. 2018) was compared to radiographic response at 2 months, PSA response, and duration of time on bavdeg. A cut-off value for CTCm was determined by receiver operating characteristic curve analysis. Association of CTCm with clinical outcomes was analyzed by two-sided Fisher’s exact test. Results: Twenty patients treated with bavdeg doses ranging from 280-700 mg daily and 140-420 mg twice daily consented to pre-treatment CTC RNA expression analysis. Circulating tumor DNA analyses revealed none of the patients harbored AR T878 or H875 mutations. Six patients remained on bavdeg >6 months with clinical benefit, while 14 discontinued therapy within 6 months. Radiographic responses at 2 months were stable, progressive, and not evaluable in 10, 7, and 3 patients, respectively. A best PSA decline ≥50% (PSA50) and ≥30% (PSA30) was achieved in 3 and 4 patients, respectively. Pre-treatment CTCm score <165 was associated with stable disease at 2 months (p = 0.015) and time on bavdeg >6 months (p = 0.014). CTCm did not correlate with PSA50 (p>0.9) or PSA30 (p=0.60). Presence of AR-V7 did not correlate with radiographic response (p=0.15), PSA50 (p>0.9), PSA30 (p=0.60), or time on therapy >6 months (p=0.14). Conclusions: Pre-treatment CTCm score <165 was associated with freedom from radiographic progression at 2 months and time on bavdeg >6 months in this small study mCRPC patients without AR T878/H875 mutations. Further investigation of the CTCm biomarker is warranted in mCRPC patients treated with bavdegalutamide and potentially other AR PROTACs.
[99mTc]Tc-iPSMA SPECT/CT as an alternative to PET imaging for decision making in prostate cancer patients.
34 Background: Prostate cancer represents a strong economic and social burden in the world. Imaging, pathology report and prostate specific antigen are the cornerstone for decision making. PSMA imaging with PET/CT has demonstrated superiority over conventional imaging, however, its availability is limited in countries with emerging economies. 99mTc-based imaging is widely used and has been favored by the development of new inhibitors targeting PSMA. Methods: We analyzed retrospectively 119 men with a histopathological diagnosis of prostate cancer obtained through transrectal biopsy or with clinical suspicion due to elevated PSA levels and physical examination findings. 68 were classified as high-risk and 51 as very high-risk, and referred for staging with [99mTc]Tc-iPSMA SPECT/CT between July 2022 and July 2024. The waiting times for initiating treatment were compared with a strategy based on PET/PSMA. Also number of lesions in patients with dual imaging with [99mTc]Tc-MDP and [99mTc]Tc-iPSMA was analyzed and assessed the changes in intention to treat. Results: Mean age of patients was 69.2 y/o (range 55-89 y/o), mean PSA level of staging group was 78.5 ng/mL (range 28.5-1667 ng/mL). Waiting time for a [99mTc]Tc-iPSMA was 7.2 days (+/- 1.5 days) versus 67.5 days (+/- 11.8 days) for [18F]F-iPSMA PSMA-1007. An additional study was required in 15.1% (n=18) of patients (n=13 PET/CT [18F]F PSMA-1007, 5 abdominal magnetic resonance). 36 patients had dual studies, observing 108 lesions with [99mTc]Tc-iPSMA and 114 with [99mTc]Tc-MDP, 6 with PSMA and 12 with MDP did not show anatomical changes. These findings did not modify the clinical stage or treatment intention. Overall, 590 lesions were identified in 119 patients, 101 in prostate, 267 in bone (diffuse disease in bone was considered as a single lesion), 135 in regional lymph nodes, and 87 in non-regional lymph nodes. Size range of lymph nodes detected were 0.5 mm to 25 mm. The change in management occurred in 23% patients (n=28); the changes were from ADT alone to doublet (ADT and Docetaxel) (n=11), from Radiotherapy to the pelvis to ADT + Docetaxel (n=8), from Radiotherapy to the pelvis to triplet (ADT+ Docetaxel + ARPi) (n=5), from ADT + RT to surgery (n=2), from ADT alone to ADT + SBRT (n=2). Conclusions: [99mTc]Tc-iPSMA SPECT/CT is an efficient alternative tool to [18F]F-iPSMA PSMA-1007, the results provide sufficient information to allow a significant change in intention to treat, significantly reducing waiting times, especially in countries where equipment availability PET is limited. These results support the development of public policies that promote the use of this type of radiopharmaceuticals to expand access to the new generation imaging modality and provide a benefit in the clinical management of prostate cancer especially in countries with low PET/CT infrastructure.
Evaluation of avelumab first-line (1L) maintenance therapy and subsequent treatment (tx) in patients (pts) with locally advanced or metastatic urothelial carcinoma (la/mUC) using a large claims database in Japan: JAVEMACS-D.
700 Background: In Japan, avelumab was approved in Feb 2021 as maintenance therapy for pts with curatively unresectable UC that had not progressed after platinum-based chemotherapy (PBC) based on phase 3 data from JAVELIN Bladder 100 showing prolonged overall survival. We report initial data from JAVEMACS-D, a real-world study of pts who received avelumab 1L maintenance therapy using a large claims database in Japan (Medical Data Vision). Methods: JAVEMACS-D is a longitudinal, observational, retrospective study of adults with la/mUC who had received PBC and had a first dose of avelumab maintenance therapy between Feb 2021 and Apr 2023. Pt characteristics and tx patterns were analyzed using descriptive statistics. Results: 773 pts were included. Median observation period was 14.0 mo from start of avelumab and 20.2 mo from start of 1L PBC. Median age was 74 y (interquartile range [IQR], 69.0-79.0), and 189 pts (24.5%) were aged ≥80 y. Primary tumor location was bladder in 463 (59.9%) and renal pelvis/ureter in 330 (42.7%). Prior 1L PBC tx was gemcitabine (gem) + cisplatin (cis) in 474 (61.3%), gem + carboplatin (carbo) in 281 (36.4%), dose-dense MVAC in 8 (1.0%), and others in 10 (1.3%). Use of 1L gem + carbo was more common in pts aged ≥80 y (101/189 [53.4%]) or pts with a primary tumor in the renal pelvis/ureter (142/330 [43.0%]) vs the overall cohort. Number of PBC cycles was ≤3 in 139 (18.0%), 4 in 260 (33.6%), 5-6 in 224 (29.0%), and ≥7 in 150 (19.4%). Avelumab therapy was started in 2021 in 289 (37.4%) and in 2022 or later in 484 (62.6%). Receipt of ≥7 cycles of 1L PBC was less common in pts who started avelumab in 2022 or later vs 2021 (80 [16.5%] vs 70 [24.2%]). Median interval between PBC and avelumab was 5.0 wk (IQR, 3.6-6.9); the interval was <4 wk in 239 (30.9%), 4-10 wk in 474 (61.3%), and >10 wk in 60 (7.8%). At data cutoff (Oct 2023), 170 (22.0%) were still receiving avelumab, 394 (51.0%) had received second-line (2L) tx, and 209 (27.0%) discontinued avelumab without 2L tx. The most common 2L tx was enfortumab vedotin (EV) in 185 of 394 pts (47.0%), gem + cis/carbo in 122 (31.0%), and pembrolizumab in 65 (16.5%); 2L EV was more common in pts who started avelumab in 2022 or later vs 2021 (123/221 [55.7%] vs 62/173 [35.8%]). The most common third-line tx after 2L EV (n=40) was pembrolizumab in 19 (47.5%) and gem + cis/carbo in 18 (45.0%). Conclusions: JAVEMACS-D provides the largest real-world dataset of pts in Japan with la/mUC treated with avelumab maintenance therapy to date. The number of prior PBC cycles was generally 6 or lower in pts who started avelumab in 2022 or later. Although pts treated with avelumab were not resistant to PBC, EV was more common than PBC as 2L tx after avelumab, particularly in pts treated more recently, highlighting the evolving tx landscape.
Phase Ib/II clinical trial of oncolytic virus intravesical irrigation for preventing recurrence after TURBT in patients with recurrent high-risk NMIBC.
763 Background: Oncolytic virus therapy represents a novel approach in cancer treatment, showing promising results in non-muscle-invasive bladder cancer (NMIBC). OH2 injection is a recombinant oncolytic virus, derived from genetically modified HSV-2 strain HG52, which is confirmed efficacy in certain malignant tumors. This clinical trial aims to evaluate the safety and preliminary efficacy of using OH2 injection solution for intravesical irrigation to prevent recurrence in patients with high-risk NMIBC who have failed first-line preventive irrigation therapy. Methods: This study included pathology confirmed high-risk NMIBC patients who had undergone TURBT after failing first-line preventive bladder irrigation therapy and had been confirmed to be free of tumor residue. To be eligible for enrollment, patients needed to have adequate organ function, an ECOG performance status of 2 or less, and be ineligible for or refused radical cystectomy. Those with muscle invasive or locally advanced metastatic bladder cancer were excluded. Following enrollment, patients received OH2 with normal saline intravesical irrigation. The irrigation was given every two weeks for 5 times, followed the sixth irrigation after 3 weeks, then once a month till a year. We evaluated the 6-month and 12-month recurrence-free survival (RFS) rates and safety following the administration of oncolytic virus irrigation during the induction and maintenance treatment. Results: Thirty patients were planned to enroll in this clinical trial. The data of 9 high risk NMIBC patients could be analyzed at this time. Most of the patients (6 out of 9) received BCG treatment before. The 6-month RFS rate was 66.7%, the 12-month RFS rate was 55.6%, and the median RFS was 353 days. One patient who failed after the BCG treatment had the long RFS nearly 2 years. In terms of safety, adverse effects observed were consistent with the known safety profile of the agent. The most common complain included transient genitourinary symptoms which might be due to TURBT. The symptoms did not worsen during the treatment process. No significant adverse effects related to OH2 irrigation was observed. Conclusions: OH2 injection is independently developed domestically and is the first in China to be used for intravesical irrigation therapy for recurrent high-risk NMIBC, particularly in patients who have failed BCG therapy. According to our data, OH2 injection intravesical irrigation is safe. The long term efficacy deserves further research. Clinical trial information: NCT05232136 .
Multivisceral surgery in patients with locally advanced castration-naïve and castration-resistant, symptomatic prostate cancer.
176 Background: Local complications due to infiltration and compression of adjacent organs represent significant complications of locally advanced castration sensitive (CSPC) and castration resistant PCA (CRPC) despite the use of life prolonging agents. Methods: 139 patients with locally advanced CSPC/CRPC underwent palliative pelvic surgery: radical cystoprostatectomy in n=105 (75.5%), radical prostatectomy with continent vesicostomy in n=9 (6.5%) and anterior plus posterior exenteration in n=25 (17.6%). All patients underwent local staging via MRI of the small pelvis, cystoscopy and rectoscopy. Systemic staging was done with CT scans of the chest, abdomen, pelvis and bone scans. Perioperative complications were assessed according to Clavien-Dindo classification and symptom-free (SFS), cancer specific survival (CSS) were evaluated using the Kaplan-Meir method. Results: Indications for surgery were lower or upper urinary tract obstruction in 75 (54%) and 55 (39%), resp., hematuria and blood transfusions in 31 (22%), rectal infiltration with/without obstructive ileus in 23 (17%), refractory pelvic pain in 17 (12%). 96 (69%) pts had a combination of various symptoms. Clavien-Dindo grade 2, 3 and 4 complications developed in 32 (23%), 12 (8.6%) and 8 (5.7%), respectively. After a median follow-up of 42.5 (3 – 123) months, the SFS at 1 and 3 years was 90.3% and 66.9%. The median SFS was 27.9 months. CSS at 1 and 3 years was 92.2% and 43.7%, respectively. 78.6% of the patients were symptom-free during their remaining lifetime. Conclusions: Multivisceral prostate surgery is a technically feasible approach in well-selected patients resulting in symptom relief of > 90% of patients which covered almost 80% of the remaining life-time. Adequate preoperative imaging studies, endoscopic evaluation and extensive surgical experience is mandatory to achieving a benefit for the individual patient with improvement of quality of life.
Assessment of pathologic responses from unstructured pathology reports using large language models.
866 Background: Emerging data suggests that Language Models (LLMs) provide an unprecedented opportunity to extract critical data from the unstructured pathology reports. However, the performance of state of art (SOTA) models on clinically meaningful tasks such as assessment of pathologic responses in patients receiving neoadjuvant chemotherapy (NAC) in muscle invasive bladder cancer(MIBC) is not well known. Methods: This retrospective cohort included patients with pathologically confirmed Muscle-Invasive Bladder Cancer from the year 2018 to 2024. Selected patients included those who underwent Neoadjuvant chemotherapy followed by definitive cystectomy at Mayo Clinic. Gold standard labels were manually curated by trained clinicians. The state of the art (SOTA) LLM – GPT4 – was utilized using a structured zero-shot prompt to extract relevant phenotypic variables such as tumor site, tumor histology and additional histological variants if any, presence of in-situ / invasive carcinoma, presence of lamina propria / muscularis propria / lympho-vascular / perineural invasion, and T-stage from unstructured pathology reports. Structured prompts were iteratively developed for each data variable and validated using ~5% of the total dataset. The extracted variables were manually compared and labelled as True positive / True negative / False positive / False negative. Final performance was assessed against a held-out expert annotated test dataset using evaluation metric (accuracy). Results: A total of 200 reports from 99 patients were extracted by the LLM. Of the 200 reports, 41 duplicate / other pathology reports (e.g. – autopsy, cholecystectomy, etc.) were removed during final assessment. Significant characteristics such as tumor site, histology, and additional histology variant had an accuracy of 89%, 87%, and 91% respectively. Notably, accuracy of detection of in-situ versus invasive carcinoma was 70% versus 91%. Specific variables such as lamina propria / muscularis propria invasion / T-stage / lympho-vascular invasion / perineural invasion were answered with the accuracy of 75%, 75%, 67%, 90%, and 94% respectively. Conclusions: LLMs have the potential to extract critical data from unstructured pathology reports and automate assessment of pathologic responses in MIBC patients receiving NAC. Iterative improvements in performance can be achieved by improving prompt design using expert clinical input. This process can be potentially scaled to automate cancer registries.
Safety profile of lutetium-177 in patients with impaired renal function: A retrospective analysis of adverse events in mCRPC treatment.
123 Background: Lutetium-177 vipivotide tetraxetan (Lu177) is the first FDA-approved radioligand therapy for PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). Not much is known regarding the safety of dosing of Lu177 in patients with creatinine clearance outside the range included in VISION trial (Sartor et al.) which was ≥50 mL/min. Using an institutional database of patients treated with Lu177, we sought to analyze whether there were increased incidences of adverse events (AEs) in patients with impaired renal function who received Lu177. Methods: We retrospectively identified 58 patients with mCRPC who received Lu177 from 2022 - 2024 at a single center (City of Hope). Impaired renal function was defined as an eGFR ≤ 60 mL/min prior to initiation of Lu177 and not confounded by acute renal injury. Statistical analysis was performed using R (v.4.4.1). A Fisher’s Exact test was used to determine whether impaired renal function was associated with increased frequency of AEs. Results: Among the 58 patients, 28 (48.28%) were Caucasian/White, 19 (32.76%) were Latino/Hispanic, 6 (10.34%) were African American/Black, and 5 (8.62%) were Asian/Pacific Islander. Median age was 68.5 years old (40-86 years old). There were 6 patients with low GFR (37 to 60 ml/min) and 36 patients with normal GFR >60 mL/min. Both groups received standard pluvicto doses. In terms of AEs, the most common AEs were anemia (41.54%), thrombocytopenia (12.31%), xerostomia (10.77%), and fatigue (10.77%). For G3/G4 AEs, the most common were anemia (56.25%) and thrombocytopenia (18.75%). Only one patient with prior impaired renal function (GFR <60 mL/min) experienced deterioration of renal function. There was no significant difference noted in incidence of AEs, incidence of anemia, and incidence of G3/G4 anemia between those with impaired renal function and those with normal function (p = 1, p = 0.7119, p = 0.6649 respectively). Conclusions: Patients with GFR < 60 mL/min did not identify an increased incidence of AEs, including anemia, when treated with Lu177. Patients with impaired GFR experienced a similar AE profile (anemia, thrombocytopenia, and xerostomia) as described in prior data sets. Our findings suggest that Lu177 may be safely dosed in patients with impaired renal function as low as eGFR 37 mL/min, without significantly increasing the risk of AEs.
Health-related quality of life in patients with metastatic prostate cancer: Results from an international real-world survey.
106 Background: Although novel treatments (tx) for metastatic prostate cancer (PC) are prolonging patient (pt) overall survival, data are limited on disease specific and general health-related quality of life (HRQoL) that can vary with pt disease stage and type of tx received. This analysis explores the HRQoL of pts diagnosed with metastatic castration-sensitive PC (mCSPC) and metastatic castration-resistant PC (mCRPC). Methods: Data were drawn from the Adelphi Real World Metastatic PC V Disease Specific Programme, an independent cross-sectional survey with retrospective data collection, of physicians and pts with mCSPC or mCRPC in France, Germany, Italy, Spain, the United Kingdom, and the United States from Nov’22 – Jul’23. Physicians reported pt demographics, clinical characteristics and tx history for their next four (mCSPC) and eight (mCRPC) consecutively seen pts. Pts voluntarily self-completed a survey including the EORTC QLQ-C30 and PR25. Pts with physician reported chart data, and an EORTC global health status/quality of life (GHS/QoL) score were included in analysis. Pt demographics, mean GHS/QoL and EORTC QLQ-C30/PR25 scale scores are reported descriptively. Results: Overall, 145 physicians reported data on 889 pts (median age 71 years (interquartile range 68 – 76), 75% ECOG 0–1, 88% had bone metastases and 24% visceral metastases). At data collection, 282 pts were receiving mCSPC tx, 482 first line (1L) mCRPC tx and 125 second line or later (2L+) mCRPC tx. Mean (SD) GHS/QoL scores for pts receiving mCSPC, 1L mCRPC and 2L+ mCRPC tx were 58.3 (19.9), 57.8 (17.7) and 55.5 (20.1) respectively, where high scores show high HRQoL. Of the symptom scales, pain was notable with mean (SD) scores of 29.9 (22.8) in mCSPC, 30.3 (20.6) in 1L mCRPC and 38.6 (23.6) in 2L+ mCRPC where high scores show worse symptomology. EORTC QLQ-C30/PR25 function scale scores are shown (Table). Conclusions: In pts who received life prolonging therapies for mCSPC and mCRPC, those with more advanced disease reported low HRQoL scores and high pain levels, suggesting that HRQoL remains an unmet need within the advanced disease setting. Metastatic prostate cancer patient EORTC QLQ-C30/PR25 function scale response. Function scales*mean (SD) mCSPC txn=282 1L mCRPC txn=482 2L+ mCRPC txn=125 Physical functioning 75.3(21.0) 75.7(18.7) 72.5(21.1) Role functioning 68.0(26.7) 69.3(23.7) 61.8(23.8) Emotional functioning 73.6(21.0) 75.9(20.6) 66.2(21.5) Cognitive functioning 80.0(21.9) 81.1(20.4) 77.0(21.8) Social functioning 75.0(24.2) 74.8(22.7) 65.5(25.7) Sexual activity 81.1(24.3) 81.4(23.9) 78.1(28.1) Sexual functioning 54.5(22.6) 57.2(21.1) 48.5(27.9) *High scores show high functioning. 1L: first line; 2L+: second line and later; mCSPC: metastatic castration-sensitive prostate cancer; mCRPC: metastatic castration-resistant prostate cancer; SD: standard deviation; tx: treatment.
Real-world outcomes of nadofaragene firadenovec in BCG-unresponsive non-muscle invasive bladder cancer.
716 Background: Nadofaragene firadenovec is an FDA-approved gene therapy for Bacillus Calmette-Guérin (BCG) unresponsive non-muscle invasive bladder cancer (NMIBC) with promising clinical trial results. However, real-world post-marketing efficacy or safety data remain lacking. We evaluated complete response rates and safety in a multisite experience. Methods: Per IRB protocol, we analyzed patients treated with nadofaragene firadenovec for BCG-unresponsive NMIBC across three Mayo Clinic sites. Outcomes included complete response (CR), high-grade recurrence-free survival (HGRFS), cystectomy-free survival (CFS), overall survival (OS), and adverse events (AEs). CR and HGRFS were reported for patients with carcinoma in situ (CIS) and patients with Ta/T1 without CIS respectively. Failure to retain was defined as any medication loss, including leakage around the catheter or early voiding. Results: Between November 2023 and October 2024, 45 patients were treated with nadofaragene firadenovec for BCG-unresponsive NMIBC. Fifteen patients with follow-up less than 6 months and one patient with extensive metastatic disease identified one week after first instillation were excluded from efficacy analysis. Our efficacy-evaluable population of 29 patients with median follow-up of 8.2 months is summarized in the Table. CR/HGRFS at 3 and 6 months was 72% and 62% respectively. CFS was 94% and OS was 100% at 6 months. Three patients experienced disease progression during follow-up: one to T1, another to T2, and a third with metastases to the abdomen and lungs. A separate patient developed a metachronous upper tract urothelial carcinoma (pT2) without bladder recurrence. Bladder spasms (62%) and failure to retain (31%) were the most common AEs. Most AEs were low-grade, although four (9%) patients had grade 3 events (fatigue, fever, and dizziness). No grade 4-5 AEs were reported. Conclusions: Early real-world data demonstrates encouraging clinical complete response rates in patients with BCG-unresponsive NMIBC and a favorable safety profile. Further investigation with larger cohorts and longer follow-up is warranted. Evaluable patients (N=29) CIS cohort (N=15) Ta/T1 only cohort (N=14) Prior pembrolizumab (N=9) Prior intravesical chemotherapy (N=16) Age, years 72 (67-77) 74 (69-77) 71 (67-77) 69 (67-78) 73 (67-81) Elixhauser Index 5 (4-6) 5 (4-7) 5 (4-6) 5 (3-5) 5 (3-6) Prior BCG instillations 12 (10-14) 12 (12-15) 11 (8-13) 12 (12-12) 12 (11-13) Prior intravesical chemotherapy among recipients 6 (6-11) 6 (6-10) 6 (6-11) 10 (7-12) 6 (6-11) Prior pembrolizumab doses among recipients 7 (4-8) 8 (7-8) 4 (4-4) 7 (4-8) 8 (5-8) Follow-up, months 8.2 (6.9-9.5) 7.6 (6.9-9.5) 8.5 (6.9-9.4) 9.1 (8.0-10.1) 8.6 (6.7-9.9) 3-month CR/HGRFS 72% [53-87] 73% [45-92] 71% [42-92] 67% [30-93] 56% [30-80] 6-month CR/HGRFS 62% [42-79] 67% [38-88] 57% [29-82] 44% [14-79] 44% [20-70] Data are median (IQR) or % [95% CI].
Mature phase 1 follow up of alpha emitter 225Ac-J591 with 177Lu-PSMA-I&T in advanced prostate cancer.
185 Background: Targeted radionucleotide therapy (TRT) has become a standard of care. α-emitters have a higher energy transfer over a shorter range than β-emitters. PSMA-targeting antibodies have different biodistribution than small molecules and may improve intracellular retention based on pre-clinical models. Here, we present mature follow up of a phase 1 dose-escalation trial of 225Ac-J591 plus 177Lu-PSMA-I&T (aka PNT2002). Methods: Inclusion criteria:progressive mCRPC with ≥1 prior AR pathway inhibitor (ARPI), prior chemo (or unfit/refused), and with ≥1 lesion on PSMA PET where SUVmax >liver. 177Lu-PSMA-I&T (6.8 GBq) and 225Ac-J591 (30, 35, or 40 KBq/kg) given up to 2 doses 8 weeks apart. Primary outcome was dose-limiting limiting toxicity and recommended phase 2 dose (RP2D). Preliminary efficacy outcomes examined were overall survival (OS), progression-free survival (PFS), PSA response, and circulating tumor cell (CTC) changes. Results: 18 patients (6 at each dose level) with median age 70, median PSA of 54.4 (2.43-9614). Previous therapies: 11 (61%) with >1 ARPI, 12 (67%) chemo, 5 (28%) sip-T, 3 (17%) radium-223. Baseline CTCs: 15 detectable, 9 unfavorable. The median SUVmax of the most avid lesion on PSMA-PET was 31.4 (95% CI 11-82.7). Metastatic sites: 13 bone, 9 lymph node, 4 visceral. 8 (44%) were Halabi high risk. Treatment emergent adverse events (AEs) included neutropenia in 3 patients (17%), all Grade <2; thrombocytopenia occurred in 12 (67%) (3 GR 3); anemia in 10 (56%, 3 GR 3); 12 (67%) xerostomia (one Gr2); one (6%) with acute renal failure. Other AEs: 10 (56%) pain flare (1 Gr3 in pt with cord compression), 11 (61%) nausea (all Gr 1), 9 (50%) fatigue (all Gr 1). The RP2D of 225Ac-J591 was 35 KGBq/kg. 17 (94%) patients experienced a decline in PSA levels, with 11 out of 17 (64%) achieving PSA50 response. 4/5 patients (80%) converted from unfavorable to favorable CTC count, 4/8 (50%) from detectable to undetectable, 1 of 2 (50%) remained undetectable. Median biochemical PFS was 7.3 months (95% CI 2.7-15.8), and median OS was 29.8 mo (95% CI 7.4-NR), with 10 patients still alive at time of submission. 5 were progression free at one year, including 3 of 6 treated at RP2D. With longer follow up, no new safety signals were identified. Conclusions: The combination of PSMA-targeted alpha (via antibody) plus beta (via small molecule) was feasible. High grade AEs were rare and no new safety signals emerged with longer term follow up. Nearly all patients had PSA decline, and 5 had durable disease control off therapy. Clinical trial information: NCT04886986 .
Optimizing the strategies to perform prostate biopsy in MRI-positive patients: A systematic review and network meta-analysis.
340 Background: Prostate cancer (PCa) is the most commonly diagnosed cancer in men, and early detection is crucial for better patient outcomes. This study aimed to thoroughly compare existing biopsy schemes for patients with suspicious lesions. Methods: This study conducted a systematic review and network meta-analysis following PRISMA guidelines, evaluating 13 biopsy schemes for detecting PCa in MRI-positive patients. Data from PubMed, Embase, and Cochrane databases were examined to assess the efficacy of biopsy schemes in detecting clinically significant (csPCa) and clinically insignificant (ciPCa) prostate cancer. Results: The analysis included 188 studies involving 64637 individuals. When compared with the combination of systematic biopsy (SB) and targeted biopsy (TB) (SB+TB), ipsilateral SB with TB (ips-SB+TB) and saturation TB (≥ 6 cores TB with or without perilesional cores) had comparable detection rate of csPCa (ips-SB+TB: RR 0.94, 95%CrI 0.87, 1.0; saturation TB: RR 0.94, 95%CrI 0.89, 1.0). While, saturation SB+TB and SB saturation (> 20 cores SB) detected slightly more csPCa than SB+TB (saturation SB+TB: RR 1.04, 95%CrI 0.97, 1.11; saturation TB: RR 1.09, 95%CrI 0.93, 1.29). And TB and SB alone detected significantly less csPCa than SB+TB (TB: RR 0.86, 95%CrI 0.84, 0.88; SB: RR 0.74, 95%CrI 0.72, 0.76). Saturation SB also did not show significant superiority in detecting csPCa. Additionally, saturation TB and ips-SB+TB also decrease the detection of ciPCa. (ips-SB+TB: RR 0.87, 95%CrI 0.73, 1.04; saturation TB: RR 0.81, 95%CrI 0.70, 0.94). The SUCRA results are detailed (Table). Conclusions: The network meta-analysis underscores that saturation SB+TB and SB+saturation TB can detect the most PCa. While, ips-SB+TB and saturation TB are effective biopsy strategies for MRI-positive PCa patients, offering a more targeted approach, improving diagnostic accuracy. Ranking probability of different biopsy schemes. PCa csPCa ciPCa Biopsy schemes Cumulative Probability Biopsy schemes Cumulative Probability Biopsy schemes Cumulative Probability 1 SB+saturation TB 0.936 SB+saturation TB 0.954 SB+saturation TB 0.958 2 saturation SB+TB 0.920 saturation SB+TB 0.922 saturation SB+TB 0.910 3 SB+TB 0.840 SB+TB 0.842 saturation SB 0.768 4 ips-SB+TB 0.621 ips-SB+TB 0.682 SB+TB 0.739 5 saturation SB 0.590 saturation TB 0.675 ips-SB+TB 0.520 6 saturation TB 0.536 non-targeted SB+TB 0.549 con-SB+TB 0.427 7 non-targeted SB+TB 0.524 saturation SB 0.489 non-targeted SB+TB 0.424 8 con-SB+TB 0.470 con-SB+TB 0.487 SB 0.392 9 TB 0.240 TB 0.401 saturation TB 0.381 10 SB 0.229 SB 0.250 ips-SB 0.306 11 ips-SB 0.096 ips-SB 0.143 con-SB 0.089 12 con-SB 0.000 adjacent sextant SB 0.108 TB 0.085 13 con-SB 0