Genitourinary oncology is no longer evolving, it is accelerating.
At ASCO GU 2026, the conversation was not simply about incremental gains. It was about movement: therapies shifting earlier, biomarkers guiding escalation, radiation partnering with immunotherapy, hypoxia signaling entering the adjuvant arena, and radioligand therapy pushing into first-line disease.
Across prostate, bladder, and renal cell carcinoma, several trials stood out not only for statistical promise, but for strategic disruption. These are not just studies. They are potential inflection points.
Here are ten trials from ASCO GU 2026 that carry the highest probability of reshaping clinical standards.
BLADDER CANCER: Moving Beyond Cisplatin
1. KEYNOTE-B15 / EV-304
Perioperative Enfortumab Vedotin + Pembrolizumab vs Gemcitabine/Cisplatin
For two decades, cisplatin-based chemotherapy has defined perioperative treatment in muscle-invasive bladder cancer (MIBC) (Grossman et al., 2003, NEJM). Yet cure rates plateau, and nearly half of patients are cisplatin-ineligible.
Then came EV-302.
In metastatic urothelial carcinoma, enfortumab vedotin (EV) plus pembrolizumab demonstrated unprecedented overall survival benefit compared with platinum chemotherapy (Powles et al., 2024, NEJM). The combination did not merely compete, it dominated.
KEYNOTE-B15 asks the natural next question: if EV + pembrolizumab is superior in metastatic disease, why wait until metastasis?
This trial compares perioperative EV + pembrolizumab against standard gemcitabine/cisplatin in resectable MIBC. If event-free survival and pathologic complete response rates are meaningfully improved, this would represent the first major displacement of cisplatin in curative-intent bladder cancer in 20 years.
This is not escalation. This is replacement.
2. IMvigor011
ctDNA-Guided Adjuvant Atezolizumab
IMvigor010 was initially considered a disappointment after adjuvant atezolizumab failed to improve disease-free survival in unselected patients (Bellmunt et al., 2021, Lancet).
But buried within the data was a signal: patients with detectable circulating tumor DNA (ctDNA) appeared to benefit.
IMvigor011 transforms that signal into strategy. Only ctDNA-positive patients are randomized to atezolizumab versus observation.
The implications are enormous. ctDNA has already demonstrated strong prognostic value in urothelial cancer (Christensen et al., 2019, JCO). If predictive capacity is validated here, bladder cancer could become the first solid tumor where adjuvant immunotherapy is routinely guided by minimal residual disease detection.
Precision adjuvant therapy would no longer be theoretical. It would be operational.
3. NIAGARA Biomarker Analyses
Liquid Biopsy in the Perioperative Setting
The NIAGARA trial previously demonstrated benefit of perioperative durvalumab in MIBC. The 2026 analyses focus on circulating and urine tumor DNA.
Bladder cancer is uniquely positioned for liquid biopsy innovation due to direct tumor–urine contact. If molecular recurrence precedes radiographic relapse reliably, adaptive treatment strategies may become possible.
This represents the transition from static staging to dynamic molecular surveillance.
PROSTATE CANCER: Earlier, Deeper, Smarter
4. PSMAaddition
177Lu-PSMA-617 Added to ADT + ARPI in mHSPC
The VISION trial changed the trajectory of metastatic castration-resistant prostate cancer (mCRPC), demonstrating improved overall survival with 177Lu-PSMA-617 after ARPI and chemotherapy (Sartor et al., 2021, NEJM).
But the field has learned a lesson over the last decade: effective drugs work better when used earlier.
PSMAaddition tests that principle directly. Radioligand therapy is added to standard androgen deprivation therapy plus AR pathway inhibition in metastatic hormone-sensitive prostate cancer (mHSPC).
Prostate cancer intensification has steadily moved forward in time, docetaxel (Sweeney et al., 2015, NEJM), abiraterone (Fizazi et al., 2017, NEJM), triplet therapy more recently.
If PSMAaddition shows significant radiographic PFS and OS benefit, radioligand therapy will join the first-line metastatic setting, years earlier than originally conceived.
That would mark one of the fastest forward shifts of a therapeutic class in oncology history.
5. PEACE-3
Radium-223 + Enzalutamide
Radium-223 demonstrated survival benefit in mCRPC with bone metastases (Parker et al., 2013, NEJM). However, combination strategies were complicated by fracture concerns.
PEACE-3 revisits radium with enzalutamide under optimized bone protection protocols.
This trial re-examines an old question with modern safeguards: can simultaneous AR pathway suppression and bone microenvironment targeting extend survival more effectively than AR blockade alone?
If positive, it restores relevance to alpha-emitting radiopharmaceuticals in combination strategies.
6. BRCAAway
PARP Inhibition + ARPI in HRR-Altered mCRPC
PARP inhibitors transformed care in DNA repair–deficient prostate cancer (de Bono et al., 2020, NEJM). The biological rationale for combining PARP inhibition with AR pathway blockade is strong, AR signaling regulates DNA repair genes.
BRCAAway evaluates this synergy.
The question is no longer whether PARP inhibitors work. It is whether earlier and broader combination improves survival beyond sequential therapy.
The outcome could reshape molecularly selected prostate cancer management.
7. CAPItello-281
AKT Inhibition in PTEN-Deficient mHSPC
PTEN loss is common in prostate cancer and activates the PI3K/AKT pathway. Targeting AKT with capivasertib represents precision pathway inhibition.
After capivasertib demonstrated efficacy in hormone receptor–positive breast cancer (Turner et al., 2023, NEJM), prostate oncology now tests similar logic.
CAPItello-281 evaluates capivasertib + abiraterone in PTEN-deficient mHSPC. Beyond efficacy, patient-reported outcomes are critical, as long-term tolerability determines real-world feasibility.
If validated, PTEN testing could become routine for treatment selection.
RENAL CELL CARCINOMA: Beyond VEGF and Checkpoints
8. LITESPARK-022
Adjuvant Belzutifan + Pembrolizumab
Adjuvant pembrolizumab improved disease-free survival in high-risk clear cell RCC (Choueiri et al., 2021, NEJM).
Belzutifan, a hypoxia-inducible factor 2α (HIF-2α) inhibitor, targets the core molecular driver of clear cell RCC — VHL pathway dysregulation (Choueiri et al., 2021, NEJM).
LITESPARK-022 combines immune checkpoint blockade with hypoxia signaling inhibition in the adjuvant setting.
This represents vertical pathway targeting in minimal residual disease. If effective, cure rates may increase, not just delay recurrence.
9. LITESPARK-011
Belzutifan + Lenvatinib vs Cabozantinib
Sequencing after immunotherapy remains an open question. Cabozantinib is the current standard (Choueiri et al., 2015, Lancet Oncol).
Belzutifan + lenvatinib combines HIF-2α inhibition with VEGF blockade. The mechanistic complementarity is compelling.
If superiority is demonstrated, second-line RCC standards may change rapidly.
10. CYTOSHRINK
Stereotactic Radiotherapy + Nivolumab/Ipilimumab
CheckMate-214 established nivolumab/ipilimumab in metastatic RCC (Motzer et al., 2018, NEJM).
CYTOSHRINK explores whether stereotactic body radiotherapy (SBRT) enhances immune response via radiation-induced neoantigen release.
The concept of immune priming through radiation has long been hypothesized. If synergy is confirmed, multimodal immune-radiation combinations may represent the next strategic frontier.
The Larger Pattern: What ASCO GU 2026 Reveals
Across diseases, several patterns emerge:
- Effective therapies are moving earlier.
- Biomarkers are determining who receives intensification.
- Radiation is being repositioned as immunologic enhancer.
- Hypoxia biology is entering mainstream RCC management.
- Radioligand therapy is shifting from salvage to frontline.
The GU field is no longer waiting for late-stage relapse before deploying its most powerful tools.
Final Perspective
The true impact of ASCO GU 2026 may not lie in any single hazard ratio.
It lies in trajectory.
KEYNOTE-B15 could end cisplatin dominance in MIBC. PSMAaddition could redefine first-line prostate cancer therapy. LITESPARK-022 may expand adjuvant RCC beyond checkpoint monotherapy. IMvigor011 could operationalize ctDNA-guided adjuvant therapy. These are not incremental refinements. They are directional shifts.
The next three years will determine whether these trials mature into new standards. But the signal from ASCO GU 2026 is unmistakable:
Genitourinary oncology is entering a precision-intensification era, earlier, smarter, and biologically anchored.
Written by Armen Gevorgyan, MD