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Erdafitinib received accelerated approval on April 12, 2019, for patients with metastatic or locally advanced urothelial carcinoma with susceptible fibroblast growth factor receptor (FGFR) 3 or FGFR2 genetic alterations and who have progressed during or following at least one platinum-based chemotherapy. It thus became the first-ever targeted therapy to receive accelerated FDA approval for metastatic bladder cancer. In the BLC2001 trial, erdafitinib demonstrated an overall response rate of 40% in patients with urothelial carcinoma. Common adverse events include hyperphosphatemia and retinopathy and require regular monitoring. While the increase in serum phosphate levels has been determined to be a pharmacodynamic marker of response, further interrogation of other clinical, genomic, and transcriptomic biomarkers is warranted. Results of the ongoing Phase III trial, THOR, which is comparing erdafitinib to the standard of care (chemotherapy or immunotherapy), are expected to confer full approval. Establishing guidelines for optimal erdafitinib sequencing with immunotherapy and other approved targeted therapies (enfortumab vedotin and sacituzumab govitecan) remains an unmet need. Keywords: advanced urothelial carcinoma, erdafitinib, fibroblast growth factor receptor, targeted therapy, patient selection

Antibody-drug conjugates (ADCs) have emerged as a promising therapeutic option, combining the specificity of monoclonal antibodies with the potency of cytotoxic payloads. While initially developed for hematologic and select solid malignancies, advances in antigen discovery, linker chemistry, and payload design have expanded their application to metastatic castration-resistant prostate cancer, where treatment options remain limited. Prostate-specific membrane antigen (PSMA), STEAP-1, TROP-2, CD46, Nectin-4, tissue factor, B7-H3, and DLL3 have emerged as clinically relevant targets, with multiple ADCs evaluated in early and late-phase trials. Although early-generation drugs were hindered by modest efficacy and significant toxicity due to linker instability and off-target effects, some novel ADCs have shown improved tolerability and encouraging antitumor activity. Ongoing studies are exploring rational combinations with hormonal, other targeted, and immune-based therapies to enhance efficacy, overcome resistance, and expand the role of ADCs in advanced prostate cancer. Herein, we provide a comprehensive overview of the clinical development of ADCs in advanced prostate cancer. Emerging treatment options in prostate cancer: Antibody-drug conjugates Antibody-drug conjugates (ADCs) are a new type of cancer treatment designed to deliver chemotherapy directly to cancer cells. Each ADC has two parts: an antibody that seeks out a marker on cancer cells, and a chemotherapy attached to it. This design allows tumors to be targeted more precisely while limiting damage to healthy cells. ADCs are now being tested in advanced prostate cancer that no longer responds to hormone therapy, a stage where treatment options are limited. Several tumor markers are being studied as targets for these medicines in clinical trials. Newer ADCs, and combinations with hormone therapy, targeted drugs, and immunotherapy, are also being explored to improve effectiveness and overcome resistance.

The most useful biomarkers for clinical decision-making identify patients likely to have improved outcomes with one treatment vs another. To evaluate treatment class-specific outcomes of patients receiving immune checkpoint inhibitor (ICI) vs taxane chemotherapy by tumor mutational burden (TMB). This comparative effectiveness analysis of clinical variables and outcomes used prospectively defined biomarker-stratified genomic data from a deidentified clinicogenomic database. Data included men with previously treated metastatic castration-resistant prostate cancer (mCRPC) receiving ICI or single-agent taxane chemotherapy from January 2011 to April 2021 at approximately 280 US academic or community-based cancer clinics (approximately 800 sites of care). Data were analyzed from July to August 2021. Single-agent ICI or single-agent taxanes. Treatments were assigned at discretion of physician and patient without randomization. Imbalances of known factors between treatment groups were adjusted with propensity weighting. Prostate-specific antigen (PSA) response, time to next therapy (TTNT), and overall survival (OS). A total of 741 men (median [IQR], 70 [64-76] years) with mCRPC received comprehensive genomic profiling and were treated with ICI or single-agent taxane therapy. At baseline, the median (IQR) PSA level was 79.4 (19.0-254) ng/mL, 108 men (18.8%) had Eastern Cooperative Oncology Group Performance Status scores of 2 or greater, and 644 men (86.9%) had received prior systemic treatments for mCRPC. A total of 45 patients (6.1%) received ICI therapy and 696 patients (93.9%) received taxane therapy. Among patients with TMB of fewer than 10 mutations per megabase (mt/Mb) receiving ICI, compared with those receiving taxanes, had worse TTNT (median [IQR], 2.4 [1.1-3.2] months vs 4.1 [2.2-6.3] months; hazard ratio [HR], 2.65; 95% CI, 1.78-3.95; P < .001). In contrast, for patients with TMB of 10 mt/Mb or greater, use of ICIs, compared with use taxanes, was associated with more favorable TTNT (median [IQR], 8.0 [3.4 to unknown] months vs 2.4 [2.4-7.3] months; HR, 0.37, 95% CI, 0.15-0.87; P = .02) and OS (median 19.9 [8.06 to unknown] months vs 4.2 [2.69 - 6.12] months; HR, 0.23; 95% CI, 0.10-0.57; P = .001). Among all 741 patients, 44 (5.9%) had TMB of 10 mt/Mb or greater, 22 (3.0%) had high microsatellite instability, and 20 (2.7%) had both. Treatment interactions with TMB of 10 mt/Mb or greater (TTNT: HR, 0.10; 95% CI, 0.32-0.31; P < .001; OS: HR, 0.25; 95% CI, 0.076-0.81; P = .02) were stronger than high microsatellite instability alone (TTNT: HR, 0.12; 95% CI, 0.03-0.51; P = .004; OS: HR, 0.38; 95% CI, 0.13-1.12; P = .08). In this comparative effectiveness study, ICIs were more effective than taxanes in patients with mCRPC when TMB was 10 mt/Mb or greater but not when TMB was fewer than 10 mt/Mb. The results add validity to the existing TMB cutoff of 10 mt/Mb for ICI use in later lines of therapy, and suggest that ICIs may be a viable alternative to taxane chemotherapy for patients with mCRPC with high TMB.

ObjectiveTo characterize and further compare the immune cell populations of the tumor microenvironment (TME) in both clear cell and papillary renal cell carcinoma (RCC) using heavy metal-labeled antibodies in a multiplexed imaging approach (imaging mass cytometry).Materials and methodsFormalin-fixed paraffin-embedded (FFPE) baseline tumor tissues from metastatic patients with clear cell renal cell carcinoma (ccRCC) and papillary renal cell carcinoma (pRCC) were retrospectively requisitioned from an institutional biorepository. Pretreated FFPE samples from 33 RCC patients (10 ccRCC, 23 pRCC) were accessioned and stained for imaging mass cytometry (IMC) analysis. Clinical characteristics were curated from an institutional RCC database. FFPE samples were prepared and stained with heavy metal-conjugated antibodies for IMC. An 11-marker panel of tumor stromal and immune markers was used to assess and quantify cellular relationships in TME compartments. To validate our time-of-flight (CyTOF) analysis, we cross-validated findings with The Cancer Genome Atlas Program (TCGA) analysis and utilized the CIBERSORTx tool to examine the abundance of main immune cell types in pRCC and ccRCC patients.ResultsPatients with ccRCC had a longer median overall survival than did those with pRCC (67.7 vs 26.8 mo, respectively). Significant differences were identified in the proportion of CD4+ T cells between disease subtypes (ccRCC 14.1%, pRCC 7.0%, p<0.01). Further, the pRCC cohort had significantly more PanCK+ tumor cells than did the ccRCC cohort (24.3% vs 9.5%, respectively, p<0.01). There were no significant differences in macrophage composition (CD68+) between cohorts. Our results demonstrated a significant correlation between the CyTOF and TCGA analyses, specifically validating that ccRCC patients exhibit higher levels of CD4+ T cells (ccRCC 17.60%, pRCC 15.7%, p<0.01) and CD8+ T cells (ccRCC 17.83%, pRCC 11.15%, p<0.01). The limitation of our CyTOF analysis was the large proportion of cells that were deemed non-characterizable.ConclusionsOur findings emphasize the need to investigate the TME in distinct RCC histological subtypes. We observed a more immune infiltrative phenotype in the TME of the ccRCC cohort than in the pRCC cohort, where a tumor-rich phenotype was noted. As practical predictive biomarkers remain elusive across all subtypes of RCC, further studies are warranted to analyze the biomarker potential of such TME classifications.

Background and objectives: Intermittent androgen deprivation therapy (iADT) may result in measurable improvements in quality of life over continuous ADT in patients with advanced prostate cancer (aPC). Here, we studied time to castration and testosterone recovery in real-world patients with aPC undergoing iADT with relugolix. Methods and design: Eligibility criteria for this retrospective study were histologically confirmed through the diagnosis of aPC and initiation of iADT with relugolix. Primary endpoints were time to castrate level of testosterone after relugolix initiation and time to recovery to noncastrate levels after relugolix discontinuation. Results: Overall, 25 patients with aPC were treated with iADT and with relugolix. Median time to serum testosterone <50 ng/dL was 1.13 months [range 0.67–2.5 months]. The median time to recovery >50 ng/dL was 1.4 months [range 0.83–6.57 months] from holding treatment with relugolix. Conclusion: iADT with relugolix is associated with a rapid time to testosterone suppression and recovery. These results may guide patients’ counseling and monitoring of serum testosterone and PSA levels in patients wishing to pursue iADT for aPC.

Background: Poly (ADP-ribose) polymerase (PARP) inhibitors are approved for patients with metastatic castration-resistant prostate cancer harboring deleterious or suspected deleterious BRCA1 and/or 2 mutations. Identifying patients with prostate cancer harboring these mutations may be challenging. Circulating cell-free DNA (cfDNA) provides an avenue for an easier detection of these mutations. Herein, we aimed to evaluate the concordance of BRCA mutations in the tumor tissue and cfDNA in patients with metastatic prostate cancer in the real-world setting. Methods: Somatic genomic profiling results were obtained from a clinical cohort of patients at our institution who had at least two samples tested. One of the samples needed to be from either primary or metastatic tissue. Concordance was adjusted to not include mutation types that the cfDNA platforms were not designed to detect. Results: The presence or absence of mutations in the BRCA gene was assessed in a total of 589 samples, including 327 cfDNA samples, from 260 patients with metastatic prostate cancer. The median time between the first test and any subsequent test was 22.8 (0.0–232) months. BRCA mutation was present in the patient’s original prostate tissue in 23 samples (3.9%) of patients. The adjusted concordance between prostate tumor tissue and cfDNA was 97.9% [95% CI, 95.3–99.1%]. The adjusted concordance between metastatic samples and cfDNA was 93.5% [95% CI, 86.4–97.3%]. Of the patients who had a BRCA mutation detected in their prostate tissue, there was a 70% probability of detecting a BRCA mutation in the patient’s cfDNA as well. For patients who did not have a detectable BRCA mutation in their primary prostate tissue, the probability of detecting a subsequent one later in the disease course was less than 0.9%. Conclusion: There is a high level of concordance between tissue and blood for BRCA mutations. Testing cfDNA can provide reliable information on BRCA mutational status and is a viable alternative to solid tissue sequencing when unavailable. The development of a new BRCA mutation later in the disease course is a rare event.

Thromboembolic events (TE) are a common complication in patients with metastatic renal cell carcinoma (mRCC) and are associated with poorer clinical outcomes. However, the incidence of TE and clinical and genomic characteristics of patients with mRCC who develop this complication are poorly understood. Herein, we describe the incidence and clinical features of patients with mRCC with or without TE at our institution, and examine their association with the underlying genomic and transcriptomic characteristics of the tumor. This retrospective study included all consecutive cases of mRCC seen at our institution. A CLIA-certified lab performed tumor genomics and transcriptomics. Patients were classified based on the presence of a TE within the first year of diagnosis. Three hundred and seventy patients with mRCC were included in the study. TE was seen in 11% (42) of the patients. Patients with favorable International mRCC Database Consortium (IMDC) risk were less likely to develop a TE. In contrast, patients receiving combination treatment with a tyrosine kinase inhibitor (TKI) and an immune checkpoint inhibitor were more likely to develop a TE. No difference in overall survival among patients with or without TE was observed (52 vs. 55 months; HR 0.85, 95% CI 0.5574–1.293, p = 0.24). The most upregulated pathways in mRCC with TEs versus those without were the xenobiotic metabolism and mTORC1 signaling pathways. Our findings suggest potential biomarkers that, after external validation, could be used to better select patients who would benefit from prophylactic anticoagulation.

Background: Accurate and efficient triage is crucial for prioritizing care and managing resources in emergency rooms. This study investigates the effectiveness of ChatGPT, an advanced artificial intelligence system, in assisting health providers with decision-making for patients presenting with metastatic prostate cancer, focusing on the potential to improve both patient outcomes and resource allocation. Methods: Clinical data from patients with metastatic prostate cancer who presented to the emergency room between 1 May 2022 and 30 April 2023 were retrospectively collected. The primary outcome was the sensitivity and specificity of ChatGPT in determining whether a patient required admission or discharge. The secondary outcomes included the agreement between ChatGPT and emergency medicine physicians, the comprehensiveness of diagnoses, the accuracy of treatment plans proposed by both parties, and the length of medical decision making. Results: Of the 147 patients screened, 56 met the inclusion criteria. ChatGPT had a sensitivity of 95.7% in determining admission and a specificity of 18.2% in discharging patients. In 87.5% of cases, ChatGPT made the same primary diagnoses as physicians, with more accurate terminology use (42.9% vs. 21.4%, p = 0.02) and more comprehensive diagnostic lists (median number of diagnoses: 3 vs. 2, p < 0.001). Emergency Severity Index scores calculated by ChatGPT were not associated with admission (p = 0.12), hospital stay length (p = 0.91) or ICU admission (p = 0.54). Despite shorter mean word count (169 ± 66 vs. 272 ± 105, p < 0.001), ChatGPT was more likely to give additional treatment recommendations than physicians (94.3% vs. 73.5%, p < 0.001). Conclusions: Our hypothesis-generating data demonstrated that ChatGPT is associated with a high sensitivity in determining the admission of patients with metastatic prostate cancer in the emergency room. It also provides accurate and comprehensive diagnoses. These findings suggest that ChatGPT has the potential to assist health providers in improving patient triage in emergency settings, and may enhance both efficiency and quality of care provided by the physicians.

Purpose of Review To provide a detailed overview of cardiovascular adverse events associated with the use of tyrosine kinase inhibitors across different tumor types. Recent Findings Despite an undeniable survival advantage of tyrosine kinase inhibitors (TKIs) in patients with hematologic or solid malignancies, the accompanying off-target cardiovascular adverse events can be life-threatening. In patients with B cell malignancies, the use of Bruton tyrosine kinase inhibitors has been associated with atrial and ventricular arrhythmias, as well as hypertension. Cardiovascular toxic profiles are heterogeneous among the several approved breakpoint cluster region (BCR)-ABL TKIS. Notably, imatinib might be cardioprotective. Vascular endothelial growth factor TKIs, constituting the central axis in the treatment of several solid tumors, including renal cell carcinoma and hepatocellular carcinoma, have strongly been associated with hypertension and arterial ischemic events. Epidermal growth factor TKIs as therapy for advanced non-small cell lung cancer (NSCLC) have been reported to be infrequently associated with heart failure and QT prolongation. Summary While tyrosine kinase inhibitors have been demonstrated to increase overall survival across different types of cancers, special consideration should be given to cardiovascular toxicities. High-risk patients can be identified by undergoing a comprehensive workup at baseline.

Background: Both novel hormonal therapies and docetaxel are approved for treatment of metastatic prostate cancer (mPC; in castration sensitive or refractory settings). Present knowledge gaps include lack of real-world data on treatment patterns in patients with newly diagnosed mPC, and comparative effectiveness of novel hormonal therapies (NHT) versus docetaxel after treatment with a prior NHT. Methods: Herein we extracted patient-level data from a large real-world database of patients with mPC in United States. Utilization of NHT or docetaxel for mPC and comparative effectiveness of an alternate NHT versus docetaxel after one prior NHT was evaluated. Comparative effectiveness was examined via Cox proportional hazards model with propensity score matching weights. Each patient’s propensity for treatment was modeled via random forest based on 22 factors potentially driving treatment selection. Results: The majority of patients (54%) received only androgen deprivation therapy for mPC. In patients treated with an NHT, alternate NHT was the most common next therapy and was associated with improved median overall survival over docetaxel (abiraterone followed by docetaxel vs. enzalutamide (8.7 vs. 15.6 months; adjusted hazards ratio; aHR 1.32; p = 0.009; and enzalutamide followed by docetaxel vs. abiraterone (9.7 vs. 13.2 months aHR 1.40; p = 0.009). Limitations of the study include retrospective design.