📬 GU Oncology Intelligence Digest — Week 2026-W38

NECTIN4 localization emerges as an enfortumab vedotin biomarker in two papers, a JAMA Network Open map finds 77.3% of US counties have no bladder cancer trial, a new CPI2 prognostic model outperforms IMDC in metastatic clear cell RCC, and baseline CEA is proposed as a prognostic marker for 177Lu-PSMA.

⚡ TL;DR

🐦 Twitter / 🦋 Bluesky

NECTIN4 localization, not just expression, separates enfortumab vedotin responders in Clinical Cancer Research — In 179 EV-treated metastatic urothelial carcinoma patients, high membranous NECTIN4 expression predicted response, PFS and OS while cytoplasmic expression did not, and amplification identified a particularly favorable subgroup
A contemporary PROTEUS-like surgical cohort of 1,392 high-risk prostate cancers shows recurrence that surgery alone does not contain — A retrospective cohort of 1,392 patients with PROTEUS-like high-risk prostate cancer treated by radical prostatectomy without neoadjuvant therapy showed substantial long-term recurrence and progression
Journal of Nuclear Medicine review counts 30 radiopharmaceutical phase 3 trials launched in five years and asks for dosimetry-driven designs — A new review of the phase 3 theranostic pipeline counts 30 RPT trials launched in the last 5 years, including PSMAcTION, STAMPEDE2, PSMA-DC, PSMAddition, NETTER-3, ACTION-1 and COMPOSE, and argues trial designs still need dosimetry and adaptive, image-guided treatment
IKCS North America Think Tank consensus asks trials to stop pooling non-clear cell kidney cancer — Consensus statements from the IKCS North America 2025 Think Tank on trials for rare kidney cancers involved 46 experts and 20 statements, with the message to move beyond pooled non-clear cell primary analyses
LUNAR reports 177Lu-PNT2002 added to SBRT more than doubles median PFS in oligometastatic prostate cancer — In the LUNAR trial, adding 177Lu-PNT2002 to stereotactic body radiation therapy improved median PFS from 7.4 to 17.6 months and prolonged hormone therapy-free survival

Full details below ↓

📄 What's Being Published

Manuscripts:

Integrating NECTIN4 Amplification With Membranous Nectin-4 Expression to Develop a Scoring System for Predicting Enfortumab Vedotin Response in Urothelial Carcinoma. — Klümper Niklas et al., Clin Cancer Res

In a retrospective analysis of 179 EV-treated metastatic urothelial carcinoma patients, high membranous NECTIN4 expression (2+/3+) predicted response with an ORR of 55.1% vs. 25.5%, PFS of 7.1 vs. 2.9 months (HR 0.45), and OS of 12.3 vs. 6.9 months (HR 0.57), while cytoplasmic expression lacked predictive value. NECTIN4-amplified tumors showed particularly favorable outcomes, with PFS of 12.2 months and OS of 30.1 months. An integrated three-tier model — amplified, non-amplified/high-membranous, and non-amplified/low-membranous — yielded ORRs of 77.2%, 42.9%, and 26.1%, and in EV-301 a H-score ≥150 cut-off corresponded to an ORR of 45.8% vs. 20% (P = 0.001).

Clinical bottom line: Nectin-4 should be scored by membranous staining and combined with NECTIN4 amplification status before enfortumab vedotin, because cytoplasmic signal adds noise rather than prediction.

Read full article →

Gemcitabine-Cisplatin Chemotherapy Induces Nectin-4 Downregulation and Enfortumab Vedotin Resistance in Bladder Cancer. — Nössing Christoph et al., Eur Urol Oncol

Using patient-derived bladder cancer models, in vitro selection for acquired gemcitabine-cisplatin resistance consistently downregulated Nectin-4 and produced enfortumab vedotin cross-resistance in resistant cells. Loss of membranous Nectin-4 expression was validated in two independent human bladder cancer cohorts — one in matched transurethral resection and radical cystectomy specimens during neoadjuvant therapy, and one in primary tumors and distant metastases during adjuvant gemcitabine-cisplatin chemotherapy. Transcriptomic profiling linked gemcitabine-cisplatin resistance and Nectin-4 downregulation to a transcriptional shift toward an epithelial-to-mesenchymal transition-like phenotype, with TGF-beta pathway vulnerabilities identified in resistant cells.

Clinical bottom line: Prior platinum chemotherapy can strip tumors of membranous Nectin-4, so Nectin-4 should be re-assessed on post-platinum tissue rather than assumed from the original resection before committing to enfortumab vedotin.

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Development and external validation of a new prognostic model for metastatic clear cell renal cell carcinoma: a preregistered analysis using data from randomised clinical trials in the checkpoint inhibitor era. — Richters Anke et al., Lancet Oncol

CPI2 was developed on 1,096 patients from CheckMate-214 and externally validated in 651 patients from CheckMate-9ER, using 14 readily available clinical parameters. Classification into three prognostic groups yielded discriminative accuracy at 36 months of 0.72 (95% CI 0.69–0.75) in CheckMate-214 and 0.72 (0.68–0.76) in CheckMate-9ER, compared with 0.65 (0.62–0.68) and 0.61 (0.57–0.65) for the IMDC classification, respectively. PD-L1 expression did not improve prognostic accuracy.

Clinical bottom line: IMDC's discrimination in the checkpoint inhibitor era is modest enough that the 14-parameter CPI2 model should now be tested in trial and observational cohorts as its replacement for risk classification in metastatic clear cell RCC.

Read full article →

🗂 Every paper considered this week, including the ones that didn’t make it →

🗣️ What People Were Discussing This Week

How these are chosen: filtered for clinical relevance, grouped by the new development discussed, then ordered by engagement (bookmarks and reposts).

NECTIN4 localization, not just expression, separates enfortumab vedotin responders in Clinical Cancer Research

Across 179 EV-treated patients with metastatic urothelial carcinoma, high membranous NECTIN4 expression predicted response, PFS, and OS, while cytoplasmic expression did not, and NECTIN4 amplification identified a particularly favorable subgroup. An earlier signal from EV-301 pointed in the same direction: patients with an IHC H-score >150 had an ORR of 45.8% vs. 20.0% with lower expression. High membranous expression (2+/3+) was associated with ORR 59% vs. 21%, mPFS 8.8 vs. 2.6 months, and mOS 13.0 vs. 8.3 months; MSKCC data presented at ASCO GU 2026 independently linked high membranous NECTIN4 with longer PFS (10 vs. 6.1 months; HR 0.55) and OS (27 vs. 19 months; HR 0.50) on enfortumab vedotin plus pembrolizumab, while higher cytoplasmic expression was not associated with better outcomes. A three-tier ordering of amplified > non-amplified/membrane-high > membrane-low tracked with ORRs of 76.2%, 42.9%, and 26.1%, sharpening the question of whether membranous re-scoring and amplification testing should precede enfortumab vedotin decisions.

Discussed by: @OncoAlert, @OncoAlert, @OncoAlert, @OncoAlert

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Sources cited: Integrating NECTIN4 Amplification With Membranous Nectin-4 Expression to Develop a Scorin… (Clin Cancer Res)

A contemporary PROTEUS-like surgical cohort of 1,392 high-risk prostate cancers shows recurrence that surgery alone does not contain

A retrospective cohort of 1,392 patients with PROTEUS-like high-risk prostate cancer undergoing radical prostatectomy without neoadjuvant therapy demonstrated substantial long-term disease recurrence and progression: biochemical recurrence-free survival declined from 60% at 3 years to 22% at 10 years, while metastasis-free survival fell to 56%, with cancer-specific survival remaining relatively high. Against that backdrop, the phase 3 PROTEUS trial of perioperative apalutamide plus ADT in 2,109 patients met both dual primary endpoints — pathologic complete response/minimal residual disease occurred in 8.9% vs. 1%, metastasis-free survival HR was 0.80, event-free survival HR was 0.71, and time to first subsequent therapy was delayed by a median of 6 years. The gap between the surgical-alone trajectory and the PROTEUS results frames a direct clinical question: given a 22% ten-year biochemical recurrence-free survival after surgery alone, which high-risk patients should now be offered perioperative apalutamide plus ADT?

Discussed by: @OncoAlert, @urotoday

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Sources cited: ScienceDirect

Journal of Nuclear Medicine review counts 30 radiopharmaceutical phase 3 trials launched in five years and asks for dosimetry-driven designs

A review co-authored with Wolfgang Fendler, David Kersting, and colleagues catalogued 30 radiopharmaceutical therapy trials launched in the last 5 years — including PSMAcTION, STAMPEDE2, PSMA-DC, PSMAddition, NETTER-3, ACTION-1, and COMPOSE — and argued that trial designs still need to embrace dosimetry and adaptive, image-guided treatment. At ProsTIC26, the fixed schedule of six cycles every six weeks for 177Lu-PSMA-617 was questioned, with response-adapted approaches using PSA, PSMA PET, SPECT/dosimetry, and ctDNA proposed to allow deep responders to pause, patients with residual disease to continue or extend therapy, and those with inadequate response to change treatment. Separately, an open-source PSMA PET/CT segmentation tool extracted lesion count, total tumor volume, and SUVmean across 1,282 patients, with these measures associated with overall survival, supporting AI-driven imaging for prognostic assessment and standardized PSMA PET reporting.

Discussed by: @urotoday, @urotoday, @urotoday

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Sources cited: pmc.ncbi.nlm.nih.gov

IKCS North America Think Tank consensus asks trials to stop pooling non-clear cell kidney cancer

Consensus statements from the IKCS North America 2025 Think Tank on trials for rare kidney cancers — developed by 46 experts and comprising 20 statements — carried a single central message: move beyond pooled "non-clear cell" primary analyses. Pitfalls in kidney cancer oncology trials were also a dedicated topic at a global renal oncology meeting, alongside discussion of access gaps in low- and middle-income countries, with the session framing the question of how rare kidney cancer trials should be powered and reported once pooled non-clear cell analyses are abandoned.

Discussed by: @PavlosMsaouel, @BourlonMaite

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Sources cited: ScienceDirect · OncoDaily

LUNAR reports 177Lu-PNT2002 added to SBRT more than doubles median PFS in oligometastatic prostate cancer

In the LUNAR trial, adding 177Lu-PNT2002 to stereotactic body radiation therapy improved median PFS from 7.4 to 17.6 months and prolonged hormone therapy-free survival, raising the question of whether radioligand therapy should be layered onto metastasis-directed therapy to address occult disease in the oligometastatic setting. Combination strategies to overcome 177Lu-PSMA-617 resistance — including AR pathway inhibitors, PARP inhibitors, immunotherapy, T-cell engagers, chemotherapy, and antibody-drug conjugates — are under evaluation, with early data supporting approaches such as enzalutamide plus Lu-PSMA, PARP-mediated radiosensitization, and Lu-PSMA plus docetaxel, though optimal sequencing, patient selection, target heterogeneity, and long-term toxicity remain unresolved.

Discussed by: @urotoday, @urotoday

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📬 GU Oncology Intelligence Digest — Week 2026-W38

⚡ TL;DR

📄 What's Being Published

🗣️ What People Were Discussing This Week

NECTIN4 localization, not just expression, separates enfortumab vedotin responders in Clinical Cancer Research

A contemporary PROTEUS-like surgical cohort of 1,392 high-risk prostate cancers shows recurrence that surgery alone does not contain

Journal of Nuclear Medicine review counts 30 radiopharmaceutical phase 3 trials launched in five years and asks for dosimetry-driven designs

IKCS North America Think Tank consensus asks trials to stop pooling non-clear cell kidney cancer

LUNAR reports 177Lu-PNT2002 added to SBRT more than doubles median PFS in oligometastatic prostate cancer

🔥 Top Ranked Tweets

🧪 Newly Recruiting Trials