Practice-changing data
The ASCO Annual Conference 2025 delivered multiple GU oncology advances including a potentially practice-changing Phase III trial in the arena of advanced prostate cancer. The Phase III AMPLITUDE trial compared niraparib combined with abiraterone acetate plus prednisone (AAP) for metastatic castration-sensitive prostate cancer (mCSPC) patients with alterations in germline/somatic homologous recombination repair (HRR) genes (BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, PALB2, RAD51B, RAD54L). Patients with HRR gene alterations were randomized 1:1 to a dual-action tablet (Niraparib 200 mg + abiraterone acetate 1000 mg) plus prednisone, or placebo + AAP, in the setting of conventional androgen deprivation therapy (ADT) to all patients. Eligible patients had received ≤6 months of ADT ± ≤6 cycles of docetaxel ± ≤45 days of AAP. Niraparib + AAP significantly improved radiographic progression-free survival (rPFS), the primary endpoint (HR, 0.63, p=0.0001), including the prespecified BRCA1/2 subgroup (HR, 0.52, p<0.0001). A trend in overall survival (OS) benefit was seen at this first interim analysis favoring niraparib + AAP (HR, 0.79, p=0.10; BRCA1/2: HR, 0.75, p=0.15). Grade 3/4 adverse events (AEs) occurred in 75.2% with niraparib + AAP and 58.9% with AAP, most commonly anemia (29.1% vs 4.6%) and hypertension (26.5% vs 18.4%). Treatment discontinuations due to AEs were low at 11.0% vs. 6.9%. Thus, data from AMPLITUDE supports niraparib + AAP as a potential new standard of care for patients with HRR–altered mCSPC. The mCSPC setting is rapidly evolving with a couple other recent news releases reporting statistically improved outcomes in separate Phase III trials: 1) addition of capivasertib to ADT + AAP demonstrated a significant rPFS improvement in patients with PTEN-deficient (by immunohistochemistry) de novo mCSPC (CAPItello-281), and 2) combination of Lutetium-PSMA with conventional ADT + AR pathway inhibitor extended rPFS accompanied by a positive trend in OS in patients with PSMA+ mCSPC (PSMAddition).
Practice-informing/affirming data
Several practice-affirming or additional analyses of previously reported Phase III trials were also presented. Data from the ARANOTE Phase III trial demonstrated that the addition of darolutamide to ADT clinically meaningful delayed deterioration of important patient-relevant health related quality of life (HRQoL) outcomes in men with mCSPC. Patients treated with darolutamide had improvements in overall well-being (FACT-P total score), social/family well-being, functional well-being, urinary symptoms, and pain. Indeed, this combination was also approved very recently by the US FDA on June 3, 2025. Previously, the FDA had already approved darolutamide in combination with docetaxel for mCSPC. An efficacy benefit was evident for talazoparib combined with enzalutamide across multiple mutational subgroups in the previously reported TALAPRO-2 Phase III trial, and was most pronounced for the BRCA1-PALB2-BRCA2 axis and CDK12, with benefit also apparent for ATM. The ARCHES Phase III trial was updated with 5-year follow-up confirming the benefit for enzalutamide combined with ADT in patients with mCSPC.
Sasanlimab in combination with BCG improved event-free survival (EFS) in patients with BCG-naive, high-risk non-muscle-invasive bladder cancer (NMIBC) who had carcinoma in situ (CIS) or T1 tumors in the CREST study. Notably, yet another trial, POTOMAC, was reported in a news release to yield improvement in disease-free survival (DFS) for the combination of durvalumab with BCG for high-risk NMIBC, but has not yet been presented at a conference. Exploratory analysis of the Phase III EV-302 trial of first-line therapy continues to strongly support enfortumab vedotin plus pembrolizumab (EV+P), given highly durable responses, especially complete responses. Tumor-informed circulating tumor DNA (ctDNA) molecular residual disease (MRD) analysis (using Signatera®) in patients with muscle-invasive bladder cancer who received perioperative durvalumab in the Phase III NIAGARA trial demonstrated benefit from durvalumab regardless of ctDNA results.
The final analysis from the Phase III CheckMate 214 trial and preliminary analysis of the Phase III PDIGREE (Alliance A031704) trial (evaluating addition of cabozantinib if stable or partial response following Nivolumab plus ipilimumab) continue to support benefit and activity of Nivolumab + ipilimumab as first-line treatment of advanced clear cell renal cell carcinoma (ccRCC). The 5-year follow-up result from the Phase III KEYNOTE-564 trial continues to support adjuvant pembrolizumab for the treatment of high-risk ccRCC following surgery.
Emerging agents and strategies
Finally, a multitude of clinical trials reported highly intriguing or emerging data supporting further development, potentially guided by precision medicine. Among them, the final results of the Phase III CheckMate 901 trial investigating previously untreated unresectable or mUC was highly intriguing. The trial evaluated nivolumab plus ipilimumab (NIVO+IPI) vs gemcitabine-carboplatin (gem-carbo) chemotherapy in the cisplatin-ineligible cohort, and NIVO+IPI vs gemcitabine-platinum (cisplatin or carboplatin) in the PD-L1-high cohort. Outcomes in these 2 cohorts were as follows: 1) Cisplatin-ineligible cohort (n=445): NIVO+IPI did not extend OS vs. Gemcitabine-Carboplatin (Gem-Carbo) (median, 19.1 mo vs 13.2 mo, HR 0.79; P = 0.0245 [required P <0.0173 for significance]), but durable responses (ORR 35.3% [CR 14.9%], median DoR 25 mo) and favorable landmark OS with NIVO+IPI suggested meaningful activity from a chemotherapy-free regimen of finite duration and treatment-free survival after CR (OS at 60 months 23% vs 14.4%). Hence, predictive biomarker guided development could be a way forward in the context of recent approval of EV+pembrolizumab for this population; 2) PD-L1-high cohort (n=250): NIVO+IPI did not extend primary endpoint OS vs. Gemcitabine-Platinum (cis or carbo) (median, 17.2 mo vs 15.2 mo, HR 0.87, P = 0.364). Another comparison of Gemcitabine-Cisplatin (GC)+NIVO has already been previously reported to improve OS in cisplatin-eligible patients, leading to regulatory approvals in many countries. Multiple promising strategies or agents were reported too.
Some of the early Phase I/II data for emerging agents or strategies include 1) in mCRPC: DB-1311/BNT324 (a novel B7H3 ADC), JNJ-78278343 (pasritamig, T-cell-redirecting bispecific T-cell engaging antibody that binds KLK2), and olaparib + radium-223 in both HRR+ and HRR- groups; 2) in mUC: sacituzumab govitecan as first-line maintenance therapy following platinum-based chemotherapy in combination with avelumab, 9MW2821 (ADC that delivers MMAE to Nectin-4+ cells) combined with toripalimab (PD1 inhibitor); and 3) in advanced RCC: casdatifan (hypoxia inducible factor [HIF]-2α inhibitor) combined with cabozantinib, zanzalintinib + nivolumab, and ALLO-316 (donor–derived allogeneic CD70 CAR T-cells).
Guru P. Sonpavde, MD is the Director of Genitourinary (GU) Oncology and Phase I Research as well as the Christopher K. Glanz Chair for Bladder Cancer Research at the AdventHealth Cancer Institute, and Professor of Medicine at the University of Central Florida, Orlando, Florida, USA. Previously, he was Bladder Cancer Director at the Dana-Farber Cancer Institute and Associate Professor of Medicine at Harvard Medical School from 2017-2022, GU Oncology Director and Associate Professor of Medicine at the University of Alabama at Birmingham from 2012 to 2017 and practiced from 2004 to 2012 at Texas Oncology, a US Oncology affiliate. His focus is drug development (including early development Phase I clinical trials and later Phase II/III trials) evaluating novel and emerging classes of treatments across solid tumors and clinical/translational research to cure GU cancers with a focus on bladder cancer.
Dr. Sonpavde has received grants from EMD Serono, Jazz Therapeutics, Bayer, Sumitomo Pharma, Blue Earth Diagnostics, and Exelixis. He has received consulting fees or honorarium from EMD Serono, BMS, Merck, Seattle Genetics, Astellas, Janssen, Bicycle Therapeutics, Pfizer, Gilead, Scholar Rock, Eli Lilly, Loxo Oncology, Vial, Aktis, Daiichi-Sankyo, Syapse, Merck, Servier, Syncorp, and Ellipses. He has also received support for travel from BMS and Astellas. He has received payment for writings from Uptodate, Practice Update, Onviv, DAVA Oncology, and PrecisCa. He has also received payment for lectures from Seagen, Gilead, Natera, Exelixis, Janssen, Astellas, Bayer, Aveo, Pfizer, and Merck. He has also received support for CME-certified speaking from Research to Practice, PeerView Institute, Ideology Health, and IBCU/Grand Rounds in Urology.
Illustration by Joe Lee
