Top 10 GU Oncology Updates: August–September 2026

The past eight weeks delivered a broad set of clinically important updates across GU Oncology. The period included full publication of two major phase 3 trials alongside regulatory action in the United States, peer-reviewed results from a pivotal bladder-sparing study, the first dedicated radiation therapy guideline in bladder cancer, and long-term randomized data in localized and biochemically recurrent prostate cancer presented at the 2026 ASTRO Annual Meeting in Boston.

This selection covers August 1 through September 30, 2026, and includes PSMAddition, LITESPARK-011, BOND-003, VOLGA, the ASTRO bladder cancer guideline, PACE-A, NRG-GU005, RTOG 3506 (STEEL), the European regulatory opinion on perioperative enfortumab vedotin plus pembrolizumab, and a CAIX-targeted PET imaging agent in renal cell carcinoma. Each item below was published, presented, formally issued, or received regulatory action during this period.

PSMAddition: [177Lu]Lu-PSMA-617 Moves Into mHSPC

Published in The Lancet on August 6, 2026, PSMAddition was a randomized, controlled, phase 3 superiority trial conducted at 169 sites across 20 countries. A total of 1,144 patients with PSMA-positive metastatic androgen pathway modulation–naive or –sensitive (hormone-sensitive) prostate cancer were assigned to six cycles of [177Lu]Lu-PSMA-617 (7.4 GBq every six weeks) added to androgen deprivation therapy plus an androgen receptor pathway inhibitor, or to ADT plus ARPI alone. The US Food and Drug Administration approved the combination on July 31, 2026, making this agent the only PSMA-targeted therapy approved across the metastatic disease spectrum.

Key findings

• At the second interim analysis, radiographic progression or death occurred in 139 of 572 patients (24%) in the radioligand arm versus 172 of 572 (30%) in the control arm (HR 0.72; 95% CI 0.58–0.90; p=0.002). The primary endpoint was met.
• Median radiographic progression-free survival was not reached in either arm; median follow-up for this endpoint was 19.6 months.
• Objective response rate was 85.3% versus 80.8%, and 87.4% versus 74.9% of patients reached a PSA nadir below 0.2 ng/mL by 48 weeks.
• Overall survival remained immature and did not reach statistical significance at this analysis (HR 0.84; 95% CI 0.63–1.13).
• Treatment delivery was feasible: 85.6% of patients in the experimental arm completed all six cycles.

Safety

Grade 3 or higher adverse events occurred in 51% of patients receiving the radioligand versus 43% with standard therapy, with cytopenias and dry mouth the expected events of interest.

Takeaway

A 28% reduction in the risk of radiographic progression or death moves PSMA-targeted radioligand therapy into first-line metastatic hormone-sensitive disease. The constraint is no longer evidence but delivery: this is a treatment that requires PSMA PET selection, nuclear medicine capacity, and radiation safety infrastructure, which will determine how widely the indication translates into practice. Mature overall survival data remain the decisive test.

LITESPARK-011: Belzutifan Plus Lenvatinib After PD-(L)1 Therapy in ccRCC

Published in The Lancet on August 12, 2026, LITESPARK-011 was an open-label, randomized phase 3 trial in 747 patients with advanced clear cell renal cell carcinoma that progressed on or after anti–PD-1/PD-L1 therapy. Patients received belzutifan 120 mg plus lenvatinib 20 mg daily or cabozantinib 60 mg daily. The FDA approved the combination on September 24, 2026.

Key findings

• At the second interim analysis (median follow-up 29.0 months), median progression-free survival was 14.8 months with belzutifan plus lenvatinib versus 10.7 months with cabozantinib (HR 0.70; 95% CI 0.59–0.84; one-sided p<0.0001).
• Objective response rate was 53% versus 40%, with 20 complete responses versus 4.
• Median duration of response was 23.0 months versus 12.3 months, and an estimated 50% versus 25% of responses were ongoing at 24 months.
• At the second interim analysis, estimated 24-month overall survival was 63% versus 55%, and the overall survival difference did not meet statistical significance (HR 0.85; 95% CI 0.68–1.05; p=0.061). At the final OS analysis reported with FDA approval, median overall survival was 33.7 versus 28.6 months (HR 0.85; 95% CI 0.70–1.03).

Safety

Hypoxia occurred in 15.4% of patients receiving belzutifan plus lenvatinib and in none receiving cabozantinib; anemia remains the characteristic class effect of HIF-2alpha inhibition.

Takeaway

This is the first phase 3 trial in which any regimen has improved progression-free survival against cabozantinib after checkpoint inhibition, and it establishes an all-oral, non–VEGF-monotherapy option in the post–PD-1/PD-L1 setting. Two practical caveats apply: overall survival was not statistically significant at the final analysis, and the toxicity profile shifts the monitoring burden toward haemoglobin and oxygen saturation, which has implications for centres without ready access to pulse oximetry follow-up or transfusion support.

VOLGA: Durvalumab Plus Enfortumab Vedotin Gains FDA Priority Review in MIBC

On September 25, 2026, the FDA granted priority review to perioperative durvalumab in combination with neoadjuvant enfortumab vedotin for patients with muscle-invasive bladder cancer who are ineligible for or decline cisplatin, with a target action date in the fourth quarter of 2026. The application is based on the phase 3 VOLGA trial, which randomized 695 patients to durvalumab plus neoadjuvant enfortumab vedotin, durvalumab plus tremelimumab with neoadjuvant enfortumab vedotin, or radical cystectomy with or without approved adjuvant therapy.

Key findings

• At a planned interim analysis, perioperative durvalumab plus neoadjuvant enfortumab vedotin significantly improved both event-free survival and overall survival versus surgery with or without adjuvant therapy.
• The tremelimumab-containing arm met the event-free survival endpoint and showed a favourable overall survival trend that did not cross the prespecified boundary at interim analysis.
• No new safety signals were reported; toxicity was consistent with the known profiles of each agent.
• Detailed efficacy data have not yet been presented at a scientific meeting.

Takeaway

If approved, this would be the first perioperative regimen in which the antibody-drug conjugate is given only before surgery, with checkpoint blockade continued afterwards — a structurally different approach from the regimen approved in July for cisplatin-eligible disease. For cisplatin-ineligible patients, who have historically received surgery alone, this is a substantive change. Full data, including pathologic complete response rates and the magnitude of the overall survival gain, are needed before the arms can be compared.

BOND-003: Durable Responses With Cretostimogene in BCG-Unresponsive NMIBC

Published in the August 2026 issue of The Lancet Oncology, Cohort C of the pivotal phase 3 BOND-003 trial evaluated intravesical cretostimogene grenadenorepvec, a conditionally replicating oncolytic adenovirus carrying a GM-CSF transgene, in 110 efficacy-evaluable patients with high-risk, BCG-unresponsive non–muscle-invasive bladder cancer with carcinoma in situ. Patients received six weekly instillations with maintenance, and re-induction was permitted for persistent disease at three months.

Key findings

• Complete response at any time was achieved in 83 of 110 patients (75.5%; 95% CI 66.3–83.2), meeting the primary endpoint; 14 complete responses followed re-induction.
• Landmark complete response rates were 46.4% at 12 months and 41.8% at 24 months.
• Among responders, the estimated probability of remaining in complete response was 64.2% at 12 months and 60.1% at 24 months, with a median duration of response of 27.9 months.
• Cystectomy-free survival was approximately 89% at 12 months and 81% at 24 months, and 96% to 97% of patients remained free of progression to muscle-invasive disease at 24 months.

Safety

No grade 3 or higher treatment-related adverse events were reported, and 97.3% of treated patients completed protocol-defined therapy.

Takeaway

The combination of a 75% complete response rate, a median response duration approaching 28 months, and no reported grade 3 or higher treatment-related adverse events supports cretostimogene as a bladder-preserving option in BCG-unresponsive carcinoma in situ. The relevant clinical question is shifting from whether bladder preservation is achievable to how to sequence the growing number of intravesical options, and how long a patient should be kept on bladder-sparing therapy before cystectomy is reconsidered.

ASTRO Issues First Radiation Therapy Guideline for Bladder Cancer

Published online in Practical Radiation Oncology on September 15, 2026 and announced by ASTRO the following day, this is ASTRO’s first guideline focused specifically on radiation therapy across the bladder cancer continuum. It was developed by a multidisciplinary task force of radiation, medical, and urologic oncologists with a medical physicist and a patient representative, in collaboration with ASCO and with endorsement from the European Association of Urology, and is based on a systematic review of evidence published from 2009 through 2024.

Key recommendations

• For appropriately selected patients with cT2–4aN0M0 muscle-invasive bladder cancer, trimodal therapy is recommended as an alternative to radical cystectomy.
• For cN1M0 disease, trimodal therapy or radical cystectomy is recommended after neoadjuvant or induction systemic therapy; for cN2–3M0 disease that is stable or responding, consolidative local therapy is conditionally recommended.
• Maximal transurethral resection before chemoradiation and concurrent radiosensitizing systemic therapy are both recommended, with neoadjuvant or induction systemic therapy for patients at higher risk of distant progression.
• Whole-bladder radiation to full dose, or reduced dose to the uninvolved bladder with a partial tumour boost, is strongly recommended, delivered with IMRT and daily image guidance.
• Postoperative radiation may improve local control after cystectomy, and a neobladder does not preclude it. Bladder-directed radiation is recommended for symptomatic disease but not for asymptomatic, high-volume metastatic disease.

Takeaway

The guideline formalizes what many multidisciplinary teams already practise but inconsistently offer: bladder preservation presented as a curative option alongside cystectomy rather than as a fallback for the unfit. It also makes an explicit point of the disparities in who is offered trimodal therapy, which is where the document is likely to have its greatest effect.

PACE-A: Eight-Year Outcomes With SBRT Versus Prostatectomy

Presented as a late-breaking abstract at the 2026 ASTRO Annual Meeting, PACE-A is the first randomized phase 3 trial to compare radical prostatectomy with stereotactic body radiotherapy in localized prostate cancer. A total of 123 surgically eligible men with cT1c–T2c disease, Gleason score 3+4 or lower, and PSA 20 ng/mL or less were randomized to prostatectomy or SBRT (36.25 Gy in five fractions) without androgen deprivation therapy. The co-primary patient-reported endpoints were published in 2024; this analysis reports disease control and five-year functional outcomes at a median follow-up of eight years.

Key findings

• Thirteen biochemical or clinical failure events occurred (8 after prostatectomy, 5 after SBRT); the unadjusted hazard ratio was 0.48 (95% CI 0.16–1.46; P=.18).
• Failure-free rates were 95% versus 94% at five years and 91% with SBRT versus 84% with prostatectomy at eight years.
• There were seven deaths, none from prostate cancer; eight-year overall survival was 95% with SBRT and 92% with prostatectomy.
• At five years, 48% of patients in the prostatectomy arm versus 8% in the SBRT arm reported using at least one pad daily; the bowel-domain disadvantage seen with SBRT at two years was no longer evident.
• Grade 2 or higher gastrointestinal and genitourinary toxicity was uncommon in both arms.

Takeaway

The trial is small and event-poor, so the numerical advantage for SBRT should not be over-read. No prostate cancer deaths were observed in either arm at a median follow-up of eight years, while the long-term differences in patient-reported function remain important considerations during treatment counselling.

NRG-GU005: Five-Fraction SBRT Versus Moderately Hypofractionated IMRT

Published in JAMA in August 2026, NRG-GU005 was an international, open-label, randomized phase 3 trial at 136 centres in the United States, Canada, Europe, and Asia. A total of 698 patients with favorable intermediate-risk prostate cancer were randomized to five-fraction SBRT or moderately hypofractionated IMRT, with co-primary endpoints of patient-reported urinary irritative/obstructive quality of life and disease-free survival.

Key findings

• At two years, clinically meaningful decline in urinary irritative/obstructive quality of life did not differ between arms (35.4% with SBRT versus 33.7% with IMRT; P=.68).
• Fewer patients experienced a clinically meaningful decline in bowel quality of life with SBRT (34.9% versus 43.8%; P=.03).
• The interim analysis crossed the futility boundary for disease-free survival: three-year disease-free survival was 92.1% with
• IMRT versus 88.6% with SBRT.
• PSA-defined biochemical failure was more frequent with SBRT (7.8% versus 4.2%; P=.04).
• Secondary outcomes favoured SBRT for incontinence-related quality of life, preservation of erectile function, and grade 3 or higher genitourinary adverse events.

Takeaway

Read alongside PACE-B and PACE-A, this trial supports five-fraction SBRT as a reasonable standard for low- and favorable intermediate-risk disease on tolerability grounds. The important methodological caution is that NRG-GU005 was designed for superiority, not non-inferiority, so the numerically higher biochemical failure rate with the dose used here cannot be dismissed and should temper dose de-escalation enthusiasm.

RTOG 3506 (STEEL): Enzalutamide Intensification With Salvage Radiotherapy

Also presented at the 2026 ASTRO Annual Meeting, STEEL was a multicentre randomized phase 2 trial in 188 men with biochemical recurrence after radical prostatectomy and at least one aggressive feature (Gleason 8–10, seminal vesicle invasion, pN1 disease, persistent postoperative PSA, or PSA of 0.7 ng/mL or higher). Patients received salvage radiotherapy to the prostatic fossa and pelvic nodes with 24 months of a GnRH analogue, with or without enzalutamide 160 mg daily.

Key findings

• At a median follow-up of 34.6 months, progression-free survival favoured the enzalutamide arm (HR 0.62; 80% CI 0.42–0.91; one-sided P=.052), with two-year biochemical failure rates of 11% versus 19%.
• After adjustment for aggressive features, race, and age, the hazard ratio was 0.54 (80% CI 0.36–0.80; two-sided P=.04).
• The population was genuinely high risk: 45% had pT3b disease, 22% were pN1, approximately 61% had Gleason 8–10 disease, and 72% had more than one aggressive feature.
• Only 53% of patients completed enzalutamide per protocol, 18% stopped for adverse events, and roughly one third received less than 80% of the planned dose.

Safety

Grade 3 adverse events occurred in 30% of the enzalutamide arm versus 19% of the standard arm; no seizures were reported and cardiac events were rare.

Takeaway

This is a hypothesis-generating phase 2 result with an 80% confidence interval and a post hoc biochemical failure threshold, so it does not establish a new standard. The findings support further evaluation of intensified androgen receptor blockade with salvage radiotherapy in patients with high-risk biochemical recurrence, while treatment adherence remains an important consideration for future studies.

CHMP Backs Perioperative Enfortumab Vedotin Plus Pembrolizumab in MIBC

On September 17, 2026, the Committee for Medicinal Products for Human Use issued a positive opinion recommending perioperative enfortumab vedotin plus pembrolizumab for adults with resectable muscle-invasive bladder cancer, with a European Commission decision expected in the fourth quarter of 2026. The opinion follows the FDA approval of July 10, 2026, and the phase 3 KEYNOTE-B15/EV-304 results reported in July, in which two-year event-free survival was 79.4% versus 66.2% with neoadjuvant gemcitabine-cisplatin (HR 0.53).

Takeaway: The positive CHMP opinion moves perioperative enfortumab vedotin plus pembrolizumab closer to potential authorization in the European Union following its approval in the United States. The practical questions now are reimbursement, the capacity to manage antibody-drug conjugate toxicity in surgical pathways, and what the standard of care will be in health systems where neither enfortumab vedotin nor pembrolizumab is funded in the perioperative setting.

68Ga-NYM096 Receives FDA Breakthrough Therapy and Fast Track Designations in ccRCC

On August 19, 2026, the FDA granted Breakthrough Therapy and Fast Track designations to 68Ga-NYM096, an investigational carbonic anhydrase IX–targeted radiopharmaceutical PET imaging agent being developed to distinguish clear cell renal cell carcinoma from non–clear cell lesions and to characterize indeterminate renal masses found on CT or MRI.

Key findings

• In an open-label, multicentre study presented at the 2026 ASCO Annual Meeting, 24 patients with primary or metastatic clear cell RCC underwent 68Ga-NYM096 PET/CT.
• Patient-level sensitivity, specificity, and accuracy were 100%, 90%, and 95.7%, respectively, and were essentially unchanged in the subgroup with primary renal masses.
• Uptake was substantially higher than with 18F-FDG in patients who underwent both scans (mean SUVmax 52.2 versus 5.5; P<.001), with a higher tumour-to-kidney ratio (3.3 versus 1.7; P<.05).
• Phase 1 trials are planned in China and the United States, with additional data due at the 2026 EANM Annual Congress.

Takeaway

With only 24 patients, these preliminary accuracy estimates require confirmation in larger prospective studies. The approach is intended to help characterize indeterminate renal masses identified on CT or MRI and distinguish clear cell RCC from non–clear cell lesions.

What These Updates Mean for GU Oncology

Two themes connect this period. The first is that therapies validated in late-stage disease continue to move earlier: PSMA radioligand therapy into hormone-sensitive prostate cancer, HIF-2alpha inhibition into the post–PD-(L)1 treatment setting in renal cell carcinoma, and antibody-drug conjugate–based regimens into the perioperative bladder cancer setting on both sides of the Atlantic.

The second is that the radiation oncology literature matured in parallel — the first ASTRO bladder guideline, eight-year randomized data from PACE-A, a cautionary superiority trial in NRG-GU005, and a phase 2 signal for intensified salvage in STEEL. Taken together, the limiting factor in genitourinary oncology is increasingly not whether a treatment works but whether the imaging, monitoring, and multidisciplinary infrastructure it assumes is actually available to the patient in front of us.

Written by Ahmed M. Elalfy, MD, PhD

Key references

1. Tagawa ST, Sartor O, Piulats JM, et al; PSMAddition Investigators. [177Lu]Lu-PSMA-617 in patients with PSMA-positive metastatic androgen pathway modulator-naive/sensitive prostate cancer (PSMAddition): a phase 3 randomised, controlled trial. Lancet. 2026. Published August 6, 2026. doi:10.1016/S0140-6736(26)01092-5. FDA approval issued July 31, 2026.
2. Motzer RJ, McDermott R, Park SH, et al; LITESPARK-011 Investigators. Belzutifan plus lenvatinib versus cabozantinib in patients with previously treated advanced renal cell carcinoma (LITESPARK-011): an open-label, randomised, controlled, phase 3 trial. Lancet. 2026 Aug 12. doi:10.1016/S0140-6736(26)01089-5. FDA approval issued September 24, 2026.
3. Tyson MD, Nam JK, Joshi SS, et al. Intravesical cretostimogene grenadenorepvec oncolytic immunotherapy in high-risk, BCG-unresponsive, non-muscle-invasive bladder cancer with carcinoma in situ (BOND-003 Cohort C): a single-arm, phase 3 trial. Lancet Oncol. 2026;27(8). doi:10.1016/S1470-2045(26)00194-4.
4. AstraZeneca. Perioperative durvalumab plus neoadjuvant enfortumab vedotin granted FDA priority review in muscle-invasive bladder cancer (VOLGA; NCT04960709). News release. September 25, 2026.
5. Ballas LK, Solanki AA, Baumann BC, et al. Radiation therapy for bladder cancer: an ASTRO clinical practice guideline. Pract Radiat Oncol. Published online September 15, 2026. doi:10.1016/j.prro.2026.09.001.
6. van As N, Patel J, Tree A, et al. Efficacy of radical prostatectomy versus stereotactic body radiotherapy for localised prostate cancer: results from an international phase III randomised controlled trial (PACE-A). Presented at: 2026 ASTRO Annual Meeting; September 26–30, 2026; Boston, MA. Abstract LBA 32.
7. Ellis RJ, et al. Stereotactic body radiotherapy vs moderately hypofractionated IMRT for localized intermediate-risk prostate cancer (NRG-GU005). JAMA. 2026. doi:10.1001/jama.2026.12627.
8. Posadas E, Gay HA, Pugh SL, et al. A randomized phase II study of enhanced AR blockade with enzalutamide in high-risk patients with biochemical relapse undergoing salvage radiation: final results from RTOG 3506 (STEEL). Presented at: 2026 ASTRO Annual Meeting; September 26–30, 2026; Boston, MA. Abstract 249.
9. European Medicines Agency Committee for Medicinal Products for Human Use. Positive opinion: perioperative enfortumab vedotin plus pembrolizumab in muscle-invasive bladder cancer. September 18, 2026. Supporting trial: Galsky MD, et al. N Engl J Med. 2026;395:338–348.
10. Xue Y, Yu W, Wu T, et al. [68Ga]Ga-NYM096 PET/CT in patients with primary and metastatic clear cell renal cell carcinoma: a preliminary study. J Clin Oncol. 2026;44(suppl 16):abstr 4537. FDA Breakthrough Therapy and Fast Track designations granted August 19, 2026.

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