Guru Sonpavde, GU Oncology and Phase I Clinical Trials Director, Chair of Bladder Cancer Research at AdventHealth Central Florida, Professor of Medicine at the University of Central Florida, and at Loma Linda University Health, shared a post on LinkedIn:
“The ASCO26 conference delivered practice-changing, practice-informing, and multiple emerging treatments and strategies to treat GU malignancies.
Practice-changing data
The conventional treatment for high-risk localized and locally advanced prostate cancer is up-front radical prostatectomy (RP) or radiation therapy combined with long duration androgen deprivation therapy (ADT) plus an androgen receptor pathway inhibitor (ARPI). The PROTEUS Phase 3 trial, which accrued 2,109 patients, reported positive results for a novel paradigm of the addition of six months of neoadjuvant plus six months of adjuvant apalutamide vs. placebo combined with ADT for high-risk localized and locally advanced prostate cancer undergoing RP. The trial had dual primary endpoints of pathologic complete response/minimal residual disease (pCR/MRD), defined as ypT0 or ypT2 disease with ≤5 mm residual tumor, and metastasis-free survival (MFS) by central review captured by conventional or PSMA-PET imaging, histopathology or death. Both pCR/MRD (8.9% vs. 1.0%, odds ratio of 10.17, p<0.0001) and MFS (hazard ratio [HR] 0.80, 95% CI 0.67–0.96, and p=0.02) significantly improved with the addition of apalutamide to ADT. Investigator-assessed MFS (hazard ratio of 0.74, p=0.0004) and event free survival (EFS) also improved (HR 0.71) with the addition of apalutamide. Overall survival (OS) is not mature. Toxicities were as expected with more frequent Grade 3-4 treatment-related adverse events (27.5% vs. 18.9%), dose reductions (11.2% vs. 2.3%) and dose interruptions (12.0% vs. 4.4%) in the apalutamide arm. These results support perioperative apalutamide plus ADT as a novel treatment strategy in patients with high-risk localized or locally advanced prostate cancer undergoing RP.
The TALAPRO-2 Phase 3 trial (n=599) reported a significant improvement in the primary endpoint of radiographic progression free survival (rPFS, HR, 0.481, P<0.0001) and a trend toward improved OS (HR, 0.767) in patients with docetaxel-naïve homologous recombination repair (HRR)-deficient metastatic castration sensitive prostate cancer (mCSPC) for the addition of talazoparib (PARP inhibitor) to ADT plus enzalutamide. The HR for rPFS was 0.368 in the BRCA-mutated subgroup (n=207, 34.6%) and 0.567 in the non-BRCA-mutated subgroup (n=392, 65.4%). The HRR alterations included ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, and RAD51C. Anemia (71.2%) and fatigue (28.4%) were the most frequent treatment-related adverse events (TEAEs), and 56 participants (18.7%) discontinued talazoparib due to TEAEs. This trial supports the addition of talazoparib with ADT and enzalutamide in the clinic. Notably, the addition of niraparib to ADT plus abiraterone in mCSPC with or without prior docetaxel exposure is already approved by the FDA for patients with mCSPC and BRCA2 alterations and for BRCA1/2 alterations in Europe.
Practice-informing/affirming data
Perioperative therapy employing enfortumab vedotin (EV) plus pembrolizumab for cisplatin-ineligible muscle-invasive bladder cancer (MIBC) has already been approved based on the phase 3 Keynote (KN)-905 trial. Now, no decrement of health-related quality of life analyses were seen at 18 weeks following radical cystectomy with perioperative EV plus pembrolizumab versus radical cystectomy alone in this trial, which further consolidates the role of this regimen in this population of patients. Notably, another trial, KN-B15, also demonstrated robustly improved outcomes with perioperative EV plus pembrolizumab for cisplatin-eligible MIBC, which are likely to establish this regimen across both the cisplatin-eligible and ineligible patients with MIBC. Previously, an analysis of the STAMPEDE Phase 3 clinical trial platform demonstrated preferential benefit of adding docetaxel to ADT in mCSPC with high Decipher Genomics Classifier (DGC) score or PTEN deficiency.
Now, a retrospective analysis of the ENZAMET Phase 3 clinical trial (which showed benefit for combining enzalutamide with ADT compared to ADT in mCSPC, and allowed docetaxel in both arms) showed that the benefit of docetaxel combined with ADT plus enzalutamide appears to be predicted by DGC score >0.85, a group of patients who had poor outcomes without docetaxel. Thus, a role for DGC is promising in this setting, although prospective investigation is ideally required. Updated analyses of the EV302 and POTOMAC Phase 3 trials confirmed the role of EV plus pembrolizumab as the preferred first-line therapy for metastatic urothelial carcinoma, and the improvement in disease free survival (DFS, HR 0.68) without negative impact on patient reported outcomes (PROs) with the addition of durvalumab to first-line BCG induction plus maintenance for high-risk nonmuscle-invasive bladder cancer (NMIBC).
Notably, the FDA approved durvalumab combined with BCG for high-risk NMIBC based on the results of the POTOMAC trial in May 2026. An analysis of the KN-564 clinical trial, which led to approval of adjuvant pembrolizumab for high-risk clear cell renal cell carcinoma (ccRCC), could not demonstrate the value of molecular residual disease (MRD) using tumor informed (both whole exome and whole genome) circulating tumor (ct)-DNA (Natera®). Only 5.4%–8.2% of patients had ctDNA detectable, which did confer a poor prognosis. However both the ctDNA negative and positive groups benefited from adjuvant pembrolizumab. Thus, more work needs to be done to evaluate more sensitive MRD platforms and potentially circulating KIM-1 protein to identify patients who may differentially benefit from adjuvant therapy.
The A-DREAM/Alliance A032101 Phase 2 trial evaluated treatment interruption in selected patients with mCSPC who had responded exceptionally to ADT plus an ARPI defined as PSA <0.2 ng/ml after 18–24 months of therapy. Re-initiation of therapy was triggered by PSA ≥5 ng/mL, radiographic change, or prostate cancer-related symptoms. The primary endpoint was the proportion of patients who remained treatment-free 18 months after treatment interruption with recovery of testosterone defined as ≥150 ng/dL. The primary endpoint was met since 41% remained treatment-free with testosterone recovery at 18 months after treatment interruption. Thus, a treatment holiday in mCSPC appears reasonable in selected patients with an excellent quality of response after 18–24 months of ADT plus an ARPI.
Emerging treatments
Chemoradiotherapy is offered to patients with MIBC ineligible for or refusing the perioperative therapy plus RC approach. A Phase 1/2 trial, RAD-IO, demonstrated the feasibility and promising 1-year DFS for durvalumab combined with 5FU+mitomycin-C + radiation. Phase 3 trials are investigating the value of this approach (KN992, SWOG/NRG 1806). The evidence for novel antibody drug conjugates (ADCs) continues to mount in urothelial carcinoma. A nectin-4 binding ADC with a topoisomerase-1 inhibitor payload (LY4052031) demonstrated activity in metastatic urothelial carcinoma even after prior exposure to EV, suggesting the continued relevance of the nectin-4 target after EV. Another ADC binding to nectin-4 conjugated to a topoisomerase-1 inhibitor payload (SHR-A2102) combined with a PD-L1 inhibitor (adebrelimab) exhibited promising activity as neoadjuvant therapy for MIBC.
A Phase 2 trial evaluating a novel strategy of intravesical BCG for enhancing immunogenicity combined with systemic cisplatin-based chemotherapy plus atezolizumab demonstrated promising pathologic complete response and preliminary event-free survival as neoadjuvant therapy for MIBC.
Finally, an early analysis of the SWOG S1823 case-control study demonstrated high specificity (94%) and negative predictive value (90%) for circulating micro-RNA miR371 in detecting relapses among seminoma or non-seminoma patients with early-stage germ cell tumors undergoing active surveillance. The sensitivity was 54%, false-positive rate 6%, positive predictive value 0.65, and the area under the curve was 0.75. The role of miR371 continues to evolve, and further data are needed with serial assays as well as the complementary role coupled with tumor markers βHCG and AFP.
Conclusion
Thus, ASCO 2026 successfully delivered multiple advances in the field of GU malignancies. Transformative advances will come with better knowledge of tumor biology and discovery of biomarkers to enable precision medicine. Accrual to clinical trials should be considered a preferred standard of care to expedite advances.”
