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Metastatic prostate cancer is a lethal disease with limited treatment options. Immune checkpoint inhibitors have dramatically changed the treatment landscape of multiple cancer types but have met with limited success in prostate cancer. In this review, we discuss the preclinical studies providing the rationale for the use of immunotherapy in prostate cancer and underlying biological barriers inhibiting their activity. We discuss the predictors of response to immunotherapy in prostate cancer. We summarize studies evaluating immune checkpoint inhibitors either as a single agent or in combination with other checkpoint inhibitors or with other agents such as inhibitors of androgen axis, poly ADP-ribose polymerase (PARP), radium-223, radiotherapy, cryotherapy, tumor vaccines, chemotherapy, tyrosine kinase inhibitors, and granulocyte-macrophage colony-stimulating factor. We thereafter review future directions including the combination of immune checkpoint blockade with inhibitors of adenosine axis, bispecific T cell engagers, PSMA directed therapies, adoptive T-cell therapy, and multiple other miscellaneous agents.

BackgroundAlthough the lifetime risk of melanoma is disproportionately higher in whites, blacks have a poorer overall survival with an absolute survival difference of 25%. Significant progress has been made in melanoma treatment in the past decade; however, these successes may not be available or accessible to all segments of the population.MethodsIn this review, we highlight important studies in melanoma as well as informative retrospective studies from databases and nonmelanoma cancers where appropriate.ResultsThere are no level I evidence-based studies on disparities in melanoma, and most likely there will never be, but the studies presented herein and clinical experience demonstrate that disparities in clinical outcomes from melanoma exists.ConclusionsBy becoming aware of the disparities, we can help mitigate them by engagement, education, and corrective and empowering actions through awareness campaigns, appropriate clinical trial design, encouraging participation in clinical trials, increasing the diversity of providers, and advocacy.

DNA replication is the fundamental process for accurate duplication and transfer of genetic information. Its fidelity is under constant stress from endogenous and exogenous factors which can cause perturbations that lead to DNA damage and defective replication. This can compromise genomic stability and integrity. Genomic instability is considered as one of the hallmarks of cancer. In normal cells, various checkpoints could either activate DNA repair or induce cell death/senescence. Cancer cells on the other hand potentiate DNA replicative stress, due to defective DNA damage repair mechanism and unchecked growth signaling. Though replicative stress can lead to mutagenesis and tumorigenesis, it can be harnessed paradoxically for cancer treatment. Herein, we review the mechanism and rationale to exploit replication stress for cancer therapy. We discuss both established and new approaches targeting DNA replication stress including chemotherapy, radiation, and small molecule inhibitors targeting pathways including ATR, Chk1, PARP, WEE1, MELK, NAE, TLK etc. Finally, we review combination treatments, biomarkers, and we suggest potential novel methods to target DNA replication stress to treat cancer.

In the ongoing EV-302 trial, first-line enfortumab vedotin plus pembrolizumab improved progression-free survival and overall survival versus platinum-based chemotherapy in patients with locally advanced or metastatic urothelial cancer. Patient-reported outcomes (PROs) from EV-302 are reported here. EV-302 was a phase 3, open-label, two-group, randomised global study to evaluate the combination of enfortumab vedotin plus pembrolizumab versus standard-of-care platinum-based chemotherapy (gemcitabine with cisplatin or carboplatin) in patients with previously untreated locally advanced or metastatic urothelial cancer. The study was done at 185 clinical sites in 25 countries. Eligible patients were aged 18 years and older with unresectable untreated locally advanced or metastatic urothelial cancer, were eligible for platinum-based chemotherapy, and had an Eastern Cooperative Oncology Group performance status of 2 or less. Patients were randomly assigned (1:1) to receive either enfortumab vedotin (1·25 mg/kg, intravenously) on days 1 and 8 of 3-week cycles plus pembrolizumab (200 mg, intravenously) on day 1 of each cycle; or platinum-based chemotherapy consisting of gemcitabine (1000 mg/m2, intravenously) on days 1 and 8 of each cycle plus either cisplatin (70 mg/m2) or carboplatin (area under the curve [AUC] 4·5 or 5·0 according to local guidelines) on day 1 of each 3-week cycle for up to six cycles using interactive response technology. Randomisation was stratified by cisplatin eligibility, PD-L1 expression status, and presence or absence of liver metastases. The dual primary endpoints of progression-free survival and overall survival in patients with locally advanced or metastatic urothelial cancer have been reported previously. Here, we report additional, protocol-prespecified secondary endpoint data, and statistical analysis plan-prespecified descriptive endpoints assessing patient quality of life (QOL). These endpoints related to patient functioning and symptoms and were assessed using two PRO questionnaires: the Brief Pain Inventory-Short Form (BPI-SF) and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). The PRO full analysis set comprised patients who received study treatment and completed at least one baseline PRO questionnaire. The BPI-SF and the EORTC QLQ-C30 were completed at baseline, weekly for 12 weeks, at week 14, then every 3 weeks during follow-up. Time to pain progression and mean change from baseline in BPI-SF worst pain at week 26 were protocol-prespecified secondary endpoints tested by the hierarchical gatekeeping strategy. Mean change from baseline to week 26 in EORTC QLQ-C30 and BPI-SF scale scores were analysed descriptively. The trial is registered with ClinicalTrials.gov, NCT04223856. At data cutoff on Aug 8, 2023, 886 patients were enrolled in the study, with a median duration of follow-up for survival of 17·2 months (IQR 12·5–21·7). 731 (83%) of 886 patients completed at least one PRO questionnaire at baseline and were included in the PRO full analysis set, with 376 patients treated with enfortumab vedotin plus pembrolizumab and 355 with platinum-based chemotherapy. 570 (78%) of 731 patients were male, 161 (22%) were female, and 479 (66%) patients were White. There was no significant difference in time to pain progression between treatments; hence differences in least squares mean change in BPI-SF worst pain score from baseline to week 26 with enfortumab vedotin plus pembrolizumab versus platinum-based chemotherapy were not formally tested. However, a numerical improvement from baseline up to week 26 was observed (least squares mean –0·74, SE 0·12 vs –0·36, 0·12; least squares mean difference –0·38, SE 0·13; 95% CI –0·64 to –0·12; nominal two-sided p value 0·0037). Overall least squares mean change in EORTC QLQ-C30 Global Health Status (GHS)/QOL from baseline up to week 26 favoured enfortumab vedotin plus pembrolizumab (least squares mean difference 2·54, 95% CI 0·41–4·67). In patients with moderate to severe baseline pain (worst pain score ≥5) receiving enfortumab vedotin plus pembrolizumab, there were clinically meaningful improvements from baseline up to week 26 in worst pain (least squares mean change: enfortumab vedotin plus pembrolizumab –2·96 [SE 0·22], platinum-based chemotherapy –2·43 [0·21]; least squares mean difference –0·53, 95% CI –1·03 to –0·02; nominal p=0·041) and in EORTC QLQ-C30 GHS/QOL (least squares mean change: enfortumab vedotin plus pembrolizumab 8·88 [1·53], platinum-based chemotherapy 4·11 [1·45]; least squares mean difference 4·77, 95% CI 1·24–8·29; nominal p=0·0083). Enfortumab vedotin plus pembrolizumab significantly improved survival outcomes versus platinum-based chemotherapy without detriment to GHS/QOL, pain, or functioning. Patients with moderate to severe baseline pain had clinically meaningful improvements in worst pain and GHS/QOL with enfortumab vedotin plus pembrolizumab. These data provide further evidence to support the use of enfortumab vedotin plus pembrolizumab as a preferred treatment option for patients with previously untreated locally advanced or metastatic urothelial cancer. Seagen (acquired by Pfizer in December, 2023), Astellas Pharma, and Merck Sharp & Dohme.

The treatment landscape of metastatic prostate cancer (mPCa) is rapidly evolving with the recent approvals of poly-ADP ribose polymerase inhibitors (PARPis) as monotherapy or as part of combination therapy with androgen receptor pathway inhibitors in patients with metastatic castration-resistant prostate cancer (mCRPC). Already part of the therapeutic armamentarium in different types of advanced cancers, these molecules have shaped a new era in mPCa by targeting genomic pathways altered in these patients, leading to promising responses. These agents act by inhibiting poly-ADP ribose polymerase (PARP) enzymes involved in repairing single-strand breaks in the DNA. Based on the PROfound and TRITON3 trials, olaparib and rucaparib were respectively approved as monotherapy in pretreated patients with mCRPC and alterations in prespecified genes. The combinations of olaparib with abiraterone (PROpel) and niraparib with abiraterone (MAGNITUDE) were approved as first-line options in patients with mCRPC and alterations in BRCA1/2, whereas the combination of talazoparib with enzalutamide (TALAPRO-2) was approved in the same setting in patients with alterations in any of the HRR genes, which are found in around a quarter of patients with advanced prostate cancer. Additional trials are already underway to assess these agents in an earlier hormone-sensitive setting. Future directions will include refining the treatment sequencing in patients with mCRPC in the clinic while taking into account the financial toxicity as well as the potential side effects encountered with these therapies and elucidating their mechanism of action in patients with non-altered HRR genes. Herein, we review the biological rationale behind using PARPis in mCRPC and the key aforementioned clinical trials that paved the way for these approvals.

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

Type 1 diabetes mellitus (T1DM) is a rare, but serious immune-related adverse event (irAE) of immune checkpoint inhibitors (ICIs). Our goal was to characterize treatment outcomes associated with ICI-induced T1DM through analysis of clinical, immunological and proteomic data. This was a single-center case series of patients with solid tumors who received ICIs and subsequently had a new diagnosis of T1DM. ICD codes and C-peptide levels were used to identify patients for chart review to confirm ICI-induced T1DM. Baseline blood specimens were studied for proteomic and immunophenotypic changes. Between 2011 and 2023, 18 of 3744 patients treated at Huntsman Cancer Institute with ICIs were confirmed to have ICI-induced T1DM (0.48%). Eleven of the 18 patients received anti-PD1 monotherapy, 4 received anti-PD1 plus chemotherapy or targeted therapy, and 3 received ipilimumab plus nivolumab. The mean time to onset was 218 days (range 22-418 days). Patients had sudden elevated serum glucose within 2-3 weeks prior to diagnosis. Sixteen (89%) presented with diabetic ketoacidosis. Three of 12 patients had positive T1DM-associated autoantibodies. All patients with T1DM became insulin-dependent through follow-up. At median follow-up of 21.9 months (range 8.4-82.4), no patients in the melanoma group had progressed or died from disease. In the melanoma group, best responses were 2 complete response and 2 partial response while on active treatment; none in the adjuvant group had disease recurrence. Proteomic analysis of baseline blood suggested low inflammatory (IL-6, OSMR) markers and high metabolic (GLO1, DXCR) markers in ICI-induced T1DM cohort. Our case series demonstrates rapid onset and irreversibility of ICI-induced T1DM. Melanoma patients with ICI-induced T1DM display excellent clinical response and survival. Limited proteomic data also suggested a unique proteomic profile. Our study helps clinicians to understand the unique clinical presentation and long-term outcomes of this rare irAE for best clinical management.

Abstract Background Metastatic renal cell carcinoma (RCC) can present as synchronous metastatic disease, where primary metastases are detected at the time of diagnosis, or metachronous disease, where metastases appear during follow-up after initial RCC diagnosis. The effect of time to metastasis on patient outcomes is not well characterized in the era of immune checkpoint inhibitor (ICI)-based combinations. Herein, we assess the differences in clinical outcomes between patients with synchronous and metachronous mRCC. Methods Data for mRCC patients treated with first line ICI-based combination therapies between 2014 and 2023 were retrospectively collected from two NCI-designated comprehensive cancer centers. Patients were categorized as having synchronous or metachronous disease based on the time of presentation of metastases. Synchronous disease was defined as the presence of metastases at the time of RCC diagnosis or within 3 months thereafter. The study endpoints were time to treatment failure (TTF), overall survival (OS), and disease control rate (DCR). TTF and OS were estimated by Kaplan-Meier method and compared based on the time of presentation of metastases using log-rank tests. Univariable and multivariable Cox proportional hazard models and logistic regression models were used to examine the impact of sex, IMDC risk score, histology, and age at treatment start on TTF, OS and DCR. Results A total of 223 patients (126 synchronous and 97 metachronous) diagnosed with mRCC were included in the analysis. No significant difference was seen in gender distribution or age at first line treatment between these two groups. Although not statistically significant, the synchronous group had a higher proportion of patients with non-clear cell histology compared to those with metachronous disease (21% vs. 11%, P = 0.057). The median TTF was shorter in patients with synchronous disease but did not reach statistical significance (9 vs. 19.8 months for synchronous and metachronous, respectively, HR 1.37, 95% CI [0.98, 1.92], P = 0.064). Median OS was significantly shorter in patients with synchronous disease (28.0 vs. 50.9 months, adjusted HR 2.23, 95% CI [1.36, 3.65], P = 0.001). Similarly, patients with synchronous mRCC had a lower DCR than patients with metachronous (58.7% vs 78.4%, adjusted odds ratio (OR) 0.29, 95% CI [0.13, 0.64], P = 0.002). In the multivariable analysis, synchronous disease remained an independent factor associated with worse OS and DCR. Conclusions Patients with metastatic disease at the time of RCC diagnosis who were treated with first line ICI-based combinations have a poorer OS, and worse DCR than those who develop metastatic disease during follow-up. Although further validation is needed, these findings could be valuable in designing clinical trials and selecting patients for treatment escalation and closer clinical follow-up. CDMRP DOD Funding: no

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.