GU Malignancy Recap from 2025 ASCO
Key Points
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KEYNOTE-564 data continue to reinforce the role of adjuvant pembrolizumab in renal cell carcinoma (RCC) based on overall survival (OS) benefit.
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In the AMPLITUDE trial, the niraparib combination improved progression-free survival (PFS) in homologous recombination repair (HRR)–mutated metastatic castration-sensitive prostate cancer (mCSPC).
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In ARANOTE, darolutamide improved health-related quality of life (HRQoL) metrics and PFS in patients with mCSPC.
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The NIAGARA trial showed prognostic utility of circulating tumor DNA (ctDNA) status in muscle-invasive bladder cancer (MIBC) treated with perioperative durvalumab.
The cohosts of the Oncology Brothers podcast, Rahul Gosain, MD, MBA, and Rohit Gosain, MD, invited Tian Zhang, MD, MHS, of UT Southwestern, to discuss genitourinary (GU) cancer abstracts presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting. The doctors reviewed data from the KEYNOTE-564, AMPLITUDE, ARANOTE, and NIAGARA studies.
KEYNOTE-564 Data Support Adjuvant Pembrolizumab in RCC
The doctors first discussed the KEYNOTE-564 study on adjuvant pembrolizumab in higher-risk, post-nephrectomy RCC. The trial randomized 994 patients 1:1 to receive either pembrolizumab or placebo every 3 weeks. The primary end point was disease-free survival (DFS), and the key secondary end point was overall survival (OS).
The initial analysis of KEYNOTE-564 published in 2021 showed pembrolizumab improved DFS, establishing adjuvant pembrolizumab monotherapy as the standard of care in this patient population. After longer follow-up, data presented in 2024 showed that pembrolizumab also benefited OS.
The presentation at the 2025 ASCO Annual Meeting demonstrated the OS benefit was sustained over a median follow-up of 69.5 months (range, 60.2-86.9). Specifically, adjuvant pembrolizumab in patients with RCC had a statistically significant hazard ratio for OS of 0.66 (95% CI, 0.48-0.90).
“I think the question now becomes, how do we decide which patients to pick for adjuvant pembrolizumab treatments?” Dr. Zhang said.
AMPLITUDE: Niraparib Combination in HRR-Mutated mCSPC
The AMPLITUDE trial evaluated niraparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, with abiraterone and prednisone in metastatic castration-sensitive prostate cancer (mCSPC) with HRR mutations.
AMPLITUDE enrolled patients with no prior PARP inhibitor or androgen receptor-targeting therapies and no more than 6 months of androgen deprivation therapy (ADT). The primary endpoint was radiographic PFS (rPFS), and secondary end points included time to symptomatic progression, OS, and safety.
The niraparib combination improved rPFS in all patients (hazard ratio [HR], 0.63; 95% CI, 0.49-0.80; P = .0001) and yielded an even greater benefit in the BRCA1 and BRCA2 alteration subgroups (HR, 0.52; 95% CI, 0.37-0.72; P < .0001). Given the additional benefit in specific mutations, Dr. Rahul Gosain emphasized the importance of somatic and germline testing upfront in patients with prostate cancer.
“What we also didn’t see in this analysis was subsequent treatments,” Dr. Zhang noted. “In all of these combination studies, we are always asking if combinations are better than sequential monotherapies—I think time will tell with how these patients do.”
Darolutamide HRQoL in Metastatic Prostate Cancer
Next, the doctors reviewed HRQoL data from the ARANOTE study on darolutamide in patients with metastatic hormone-sensitive prostate cancer (mHSPC). During ASCO, the FDA announced the approval of darolutamide based on previously published PFS data.
ARANOTE found that darolutamide reduced risk of rPFS by 46% (HR, 0.54; 95% CI, 0.41-0.71; P < .0001) and improved time to pain progression (stratified HR, 0.72; 95% CI, 0.54-0.96) as well as time to deterioration in Functional Assessment of Cancer Therapy–Prostate total score (stratified HR, 0.76; 95% CI, 0.61-0.94). “I think these are really encouraging results, especially adding to the rPFS primary endpoint improvement with darolutamide,” Dr. Zhang said.
Dr. Rohit Gosain asked Dr. Zhang how she selects androgen receptor pathway inhibitor therapies in her practice. Dr. Zhang said that between the three approved agents, darolutamide, apalutamide, and enzalutamide, darolutamide has some evidence for better tolerability, but the right agent is ultimately whatever is most accessible to patients.
She also noted the ongoing ARACOG trial is further examining the cognitive function side effects of darolutamide compared with enzalutamide.
Impact of ctDNA Status on Clinical Outcomes in NIAGARA
The discussion concluded by reviewing an exploratory analysis on ctDNA from the NIAGARA trial. Previously, NIAGARA reported that perioperative durvalumab improved event-free survival (EFS) and OS compared with neoadjuvant chemotherapy alone in patients with resectable MIBC.
While the earlier findings from the NIAGARA trial established the perioperative durvalumab approach as standard of care for this population, questions remained about the potential predictive value of ctDNA. Dr. Zhang said the 2025 ASCO Annual Meeting abstract reported that ctDNA positivity after surgery was associated with poorer EFS and DFS outcomes over 3 to 4 years.
Notably, perioperative durvalumab improved outcomes in patients that were ctDNA-negative, which “says to me that ctDNA is not perfect as a biomarker, but it also says that durvalumab has a benefit across populations,” she added.
For current practice, Dr. Zhang suggested that ctDNA positivity can help identify higher-risk patients who may benefit from intensified up-front treatment.