Phase 3 AMPLITUDE Trial: Niraparib (NIRA) and Abiraterone Acetate plus Prednisone (AAP) for Metastatic Castration-Sensitive Prostate Cancer (mCSPC) Patients (pts) with Alterations in Homologous Recombination Repair (HRR) Genes

Speaker: Gerhardt Attard

Introduction

The AMPLITUDE trial evaluates Niraparib (a PARP- Poly (ADP-ribose) Polymerase inhibitor) combined with Abiraterone Acetate and Prednisone (AAP) in mCSPC patients with HRR gene alterations. HRR gene alterations (especially BRCA1/2) are linked to worse prognosis. PARP inhibitors are approved in mCRPC with BRCA mutations, but their role in mCSPC was previously untested.

Study Design

• Type: Phase 3, Randomized, double-blind, placebo-controlled trial.
• Treatment arms
  • Experimental: Niraparib 200 mg QD + AAP (Abiraterone 1000 mg + Prednisone 5 mg BID)
  • Control: Placebo + AAP
  • All patients also received continuous ADT (Androgen Deprivation Therapy)
• Eligibility: mCSPC with ≥1 HRR gene alteration (e.g., BRCA1, BRCA2, CDK12, etc.)
• Stratification factors: BRCA vs CDK12 vs other HRR genes, prior docetaxel, disease volume.
• Allowed
  • ADT ≤6 months
  • Docetaxel ≤6 cycles
  • AAP ≤45 days prior to randomization
• Key Endpoints
  • Primary: Radiographic Progression-Free Survival (rPFS)
  • Secondary: Time to symptomatic progression, overall survival (interim)
  • Group-sequential hierarchical testing: BRCA-mutant population → full HRR-altered ITT (Intention-to-Treat) population

Results

Efficacy

• Primary endpoint met: rPFS improved significantly:
  • 48% risk reduction in BRCA subgroup
  • 37% risk reduction in full HRR-altered population
• Time to symptomatic progression
  • Reduced by 56% in BRCA-m group
  • Reduced by 50% in HRR-m population
• Overall survival (interim)
  • ~50% events; early trends favor Niraparib + AAP

Exploratory Subgroup Analysis

• Non-BRCA HRR genes (n=7): rPFS HR = 0.81
• Heterogeneous effects noted; not powered for formal comparison
• Future meta-analyses anticipated for clarity on gene-specific benefit

Safety Profile

• TEAEs (Grade ≥3): 59% (placebo group) vs 75% (Niraparib group)
• Discontinuation due to AEs: 15% in Niraparib group vs 10% in placebo group
• Most common AE: Anemia (29% grade 3–4); one case of MDS in a patient with germline CHEK2 mutation
• Hematologic and cardiovascular systems most affected

Clinical Implications

• AMPLITUDE is the first positive phase 3 trial showing benefit of PARP + ARPI combo in mCSPC.
• Supports
• Early HRR genomic testing at diagnosis of metastatic disease
• Individualized discussions on toxicity vs progression delay, especially in BRCA-altered patients

Conclusion

Niraparib + AAP significantly improved rPFS and time to symptomatic progression in HRR-altered mCSPC, especially BRCA-mutated cases. Safety was manageable and consistent with prior studies. The trial highlights the need for precision oncology in upfront treatment of mCSPC.

Five-year follow-up Results from the Phase 3 KEYNOTE-564 Study of Adjuvant Pembrolizumab (Pembro) for the Treatment of Clear Cell Renal Cell Carcinoma (ccRCC).

Speaker: Naomi B. Haas

Introduction

Nearly 1,000 patients with ccRCC at increased risk for recurrence were enrolled. Participants were randomized in a 1:1 ratio to receive either one year of Pembro or one year of placebo. DFS by investigator assessment was selected as the primary endpoint. Key secondary endpoints included OS and safety. All patients have completed five years of follow-up, with a landmark analysis approaching six years.

Efficacy Outcomes

DFS: A sustained separation of the Kaplan-Meier DFS curves was observed.

• HR for DFS: 0.71 (95% CI: 0.59 to 0.86).
• All subgroups were shown to favor Pembro in the DFS forest plot.

OS: A separation of OS curves was noted after adjuvant therapy and maintained over time.

•  HR for OS: 0.66 (95% CI: 0.48 to 0.9).
• Subgroup analysis consistently favored Pembro.

Pembro was identified as the only adjuvant therapy in RCC to demonstrate an OS benefit to date.

Subsequent Therapies Following Recurrence:

A total of 171 recurrences were documented in the Pembro group, and 226 in the placebo group.

• Systemic therapy alone was received by ~40% of patients in both arms.
• Combination and local therapies were also utilized.
• Use of VEGF inhibitors was found to be similar between arms.
• A higher rate of anti-PD-1 therapy use was reported in the placebo group.
• Missing or unreported data were comparable between arms.

Safety Profile

No new safety signals were identified.

• Severe adverse events (Grade ≥3) were primarily hypertension and transaminitis, followed by diarrhea.
• The duration of SAEs until resolution was assessed.
• No new serious treatment-related adverse events were reported after three or more years.

Conclusion

The sustained improvements in both disease-free and overall survival observed at five years have confirmed the long-term benefit of adjuvant Pembro in patients with high-risk ccRCC. Efficacy was maintained across subgroups, and no new safety concerns were identified, reinforcing pembrolizumab's position as a standard of care in this setting.

Ipilimumab and Nivolumab in Patients with Metastatic Clear Cell Renal Cell Carcinoma (mccRCC) Treated on the Phase 3 PDIGREE (Alliance A031704) Trial: Results from Step 1 Analysis.

Speaker: Tian Zhang

Introduction

Immunotherapy doublets such as Ipilimumab + Nivolumab (CheckMate 214) and Cabozantinib + Nivolumab (CheckMate 9ER) have been established as the standard first-line treatments for metastatic kidney cancer, particularly in patients with IMDC intermediate and poor-risk disease.

Trial Design and Objectives

The PDIGREE trial was designed to evaluate a sequential treatment approach involving Ipilimumab + Nivolumab followed by either Nivolumab maintenance or Cabozantinib + Nivolumab, based on radiographic responses at three months.

• Step One: Up to four cycles of Ipilimumab + Nivolumab were administered.
• Step Two:
• Complete responders received Nivolumab alone.
• Progressive disease cases were treated with Cabozantinib alone.
• Partial responders and those with stable disease were randomized to either Nivolumab or Nivolumab + Cabozantinib.

The primary endpoint was defined as overall survival of the randomized cohort.

Patient Enrollment and Disposition:

A total of 1,011 patients were enrolled between May 2019 and May 2024.

• By the data cut-off (January 2025), 67% had progressed to step two.
• Step Two Assignments:
• 597 patients were randomized (PR/SD cohort).
• 141 patients received Cabozantinib (PD cohort).
• 9 patients received Nivolumab (CR cohort).
• Discontinuations before Step Two (n=364):
• 160 due to non-resolving adverse events.
• 46 due to progressive disease.
• 39 pursued alternative therapies.
• 37 early deaths (15 potentially treatment-related).

Patient and Disease Characteristics:

• Median age: 64 years.
• Gender: 73% men.
• Ethnicity/Race: 10% Hispanic; over 8% identified as Black, Asian, or American Indian/Alaskan Native.
• IMDC Risk: 76.8% intermediate risk, 23% poor risk.
• Bone metastases were present in 27%.
• De novo metastatic disease was observed in 54%.
• 48% of patients were enrolled at community oncology centers.
• Fewer patients with poor-risk disease and bone metastases proceeded to step two compared to those who discontinued.

Safety Outcomes (Step One)

• Grade 3/4 treatment-related toxicities were consistent with known Ipilimumab + Nivolumab adverse effects and included diarrhea, colitis, elevated transaminases, rashes, and endocrinopathies.
• Fifteen grade 5 events (deaths) were attributed primarily to cardiac, respiratory, and hepatic failures.

Conclusion

The step one analysis of the PDIGREE trial has confirmed the relevance of immunotherapy doublets in metastatic kidney cancer. Differential step two enrollment based on IMDC risk and bone metastases was observed. Although overall survival data remain pending, the trial's adaptive treatment design and steady patient recruitment in a shifting therapeutic landscape were demonstrated.

First Results of SURE-02: A Phase 2 Study of Neoadjuvant Sacituzumab Govitecan (SG) plus Pembrolizumab (Pembro), Followed by Response-adapted Bladder Sparing and Adjuvant Pembro, in Patients with Muscle-invasive Bladder Cancer (MIBC).

Speaker: Andrea Necchi

Introduction

The SURE-02 study was developed following benchmarks set by PURE-1 and SURE-1 studies. Due to frequent patient refusal of radical cystectomy, even after clinical complete response (cCR), the initial neoadjuvant-surgery-adjuvant protocol was amended. A multidisciplinary review and re-TURBT (re-transurethral resection of bladder tumor) approach was incorporated for patients refusing cystectomy, followed by maintenance immunotherapy.

Study Design and Endpoints

• Primary Endpoint: Clinical complete response (cCR), defined as imaging complete response and negative biopsy.
• Secondary Endpoints: Multiple additional outcomes were evaluated.
• Safety Measure: An extra safety provision was applied for those refusing chemoradiation.

Patient Population and Data Status

• A total of 49 patients were enrolled and included in the safety analysis.
• Efficacy results were available for 36 patients at the time of reporting.
• Key characteristics:
• 80% refused chemoradiation.
• 64% refused neoadjuvant chemotherapy.
• 72% had residual disease at baseline.
• 38% exhibited variant histology.

Safety Outcomes

• The SG + Pembro combination (SG 7.5 mg/kg + GCSF + pembro) was generally well tolerated.
• Grade 3/4 treatment-related toxicities were observed in <20%, and immune-related toxicities in <5% of patients.
• Three patients discontinued neoadjuvant therapy due to adverse events.
• No SG dose reductions were required.

Efficacy Outcomes (Preliminary)

• Clinical Complete Response (cCR):
• Among 23 patients who underwent re-TURBT instead of cystectomy, 16 achieved pT0, yielding a cCR rate of 44.4%.
• Surgical Outcomes:
• Three delayed cystectomies were performed (none for progression).
• Two intravesical recurrences were noted in cCR patients, all remaining metastasis-free.
• Overall downstaging rate: 55.6%.
• Survival Rates
• 12-month EFS: 71.3%.
• 1-year MFS for cCR patients: 100%.
• Bladder-Intact EFS in re-TURBT patients: 74%.

Translational Findings (Preliminary)

• Genomic Alterations
• ERBB2 alterations were more common in cCR patients (40% vs. 11%).
• CDKN2A/B losses were enriched in cCR patients.
• Higher baseline TMB was associated with cCR.
• One case showed post-treatment MDM2 loss mutation.
• Transcriptomic Results
• Higher cCR rates were linked to luminal, GU, and MMR-high subtypes.
• Improved EFS was associated with higher expression of TROP2, MMR signature, and papillary subtype.
• Expression of TROP2, MMR signature, and ERBB2 was enriched in luminal tumors per Veracyte Decipher classification.
• Findings were preliminary and not fully validated.

Conclusion

A clinical complete response rate of 44% was achieved with neoadjuvant SG plus Pembro, supporting the feasibility of bladder preservation in MIBC. Preliminary translational data suggested that luminal subtype tumors may be more responsive to SG, while TMB and TAP loss may predict Pembro response. These early findings were considered promising for bladder-sparing strategies.

Predictive and Prognostic Value of Baseline PSMA-PET Total Tumor Volume and SUV Mean within ENZA-p, a Randomized Phase II trial of Enzalutamide versus Enzalutamide plus [177Lu] Lu-PSMA-617 (ANZUP1901)

Speaker: Louise Emmett

Introduction

The speaker explains that PSMA-PET total tumor volume (TTV) and SUV mean are key imaging biomarkers used to quantify tumor burden in prostate cancer. TTV involves combining all PSMA-avid tumor sites with a minimum SUVmax threshold (≥3), and is measured in milliliters. SUV mean reflects the average tracer uptake across tumor sites.

The speaker highlights prior evidence from THERAP and VISION trials, where high SUV mean correlated with better response to lutetium-PSMA monotherapy. However, little was known about how these measures perform in combination settings (e.g., with Enzalutamide), or their role in predicting outcomes with AR-targeted therapy alone — which this ENZA-p trial aimed to investigate.

Study Overview

• Trial Name: ENZA-p (ANZUP1901)
• Design: Randomized phase II trial
• Arms:
  • Enzalutamide monotherapy
  • Enzalutamide + [¹⁷⁷Lu]Lu-PSMA-617 (2 or 4 doses)
• Population: Patients with high-risk, high-volume metastatic castration-resistant prostate cancer (mCRPC) without prior chemotherapy for mCRPC
• Primary Endpoint: PSA progression-free survival (PFS)
• Secondary/Exploratory Endpoints: Overall survival (OS), PSA90 response, health-related quality of life

Key Findings

PSMA Total Tumor Volume (TTV)

• Prognostic for OS: In Enzalutamide monotherapy arm:
  • High volume: Median OS = 20 months
  • Low volume: Median OS = 39 months (HR: 0.23, p < 0.001)
• Predictive for Combination Benefit:
  • High-volume patients had improved OS when lutetium-PSMA added (20 → 28 months)
  • Significant interaction (p = 0.008)
• PSA-PFS: High-volume patients also had improved PFS (3 → 11 months) with combination
• Remained significant after adjustment for clinical variables

SUV Mean

• Not prognostic or predictive for OS or PSA-PFS when Lu-PSMA used with Enzalutamide
• Paradoxical finding: In Enzalutamide monotherapy arm, low SUV mean associated with higher PSA90 response (47% vs. 27%)

Methodology Details

• Imaging: Gallium-68 PSMA-11 PET/CT at 15 harmonized centers
• Quantification:
  • SUVmax ≥15 at one site and ≥10 at all sites for eligibility
  • SUVmean and TTV calculated using predefined thresholds
• Substudy Sample: 160 randomized, 160 analyzed; 60 patients included in imaging substudy

Rationale for Combination Therapy

• Enzalutamide upregulates PSMA in resistant clones
• Lutetium-PSMA targets high-expressing aggressive cells
• Hypothesis: Sequential targeting may prolong response to Enzalutamide in low PSMA clones

Clinical Implications

• TTV via PSMA-PET can serve as a biomarker to guide treatment intensity
• SUV mean is less reliable when Lu-PSMA is combined with AR-directed therapy
• Low SUV mean may identify patients who derive deeper responses from Enzalutamide alone

Conclusion

First trial to establish PSMA-PET total tumor volume as a prognostic and predictive marker in mCRPC. Findings support broader utility of PSMA-PET beyond monotherapy selection

ARCHES: 5-year follow-up Overall Survival (OS) Analysis of Enzalutamide (ENZA) plus Androgen-Deprivation Therapy (ADT) in Patients (pts) with Metastatic Hormone-Sensitive Prostate Cancer (mHSPC).

Speaker: Andrew Armstrong

Introduction

A 5-year follow-up OS analysis from the phase 3 global, randomized ARCHES trial was conducted in patients with mHSPC. A total of 1,150 patients were enrolled and stratified by disease volume and prior docetaxel use. Patients were randomized to receive either Enzalutamide plus ADT or placebo plus ADT. Crossover from placebo to Enzalutamide was permitted after the primary analysis. The data cut-off was July 31, 2024.

Overall Survival Outcomes

A 13% absolute improvement in 5-year OS was observed with Enzalutamide (66%) compared to placebo (53%) (Hazard Ratio: 0.70; P < 0.001). In patients with high-volume disease, median OS was extended by 35.5 months (from 47.5 to 83 months). Survival benefit was found to be consistent across subgroups, including high/low disease volume, prior docetaxel use, and synchronous or metachronous disease.

Subgroup Findings

In patients with high-volume disease, a 3-year OS extension was reported. For those with low-volume disease, median OS was not reached, although a continued separation of survival curves was noted. Among patients with prior docetaxel use, one of the greatest benefits was recorded. The benefit of Enzalutamide was consistently observed across age, race, geographic region, ECOG performance status, and PSA levels.

Safety and Adverse Events

Grade 3–4 adverse events were reported more frequently in the Enzalutamide arm. No difference in Grade 5 adverse events was observed between treatment arms. Commonly reported adverse events included hypertension, fatigue, falls, cognitive impairment, and fractures. Most adverse events occurred in the first year and declined significantly from years 2 to 5. No new safety signals were identified at the 5-year follow-up.

Limitation

This was a post hoc analysis with nominal p-values. Median OS was not reached in some subgroups. The estimation of treatment effect may have been diluted due to crossover and the commercial availability of androgen receptor inhibitors.

Conclusion

A sustained overall survival benefit of Enzalutamide plus ADT over 5 years was confirmed in patients with mHSPC, particularly in those with high-volume disease. Adverse events were found to be manageable and declined over time, supporting the long-term use of this treatment regimen.

Docetaxel with Androgen Deprivation Therapy (ADT) and Radiotherapy (RT) for High-risk Localized Prostate Cancer (HRLPC): An ICECaP Individual Patient-data (IPD) Meta-analysis of Randomized Controlled Trials (RCTs).

Speaker: Praful Ravi

Introduction

Dr. Praful presented an individual patient data meta-analysis conducted to assess whether the addition of docetaxel to ADT and RT for high-risk localized prostate cancer (HRLPC) improved patient survival. Earlier ICECaP analyses demonstrated that patients with 2-3 high-risk factors—including, Gleason ≥8, PSA >20 ng/mL, clinical stage T3-4, or positive lymph node — had worse outcomes with standard treatment, with 5-year metastasis-free survival (MFS) below 80%. 

Methods

• The analysis integrated data from four randomized controlled trials: GETUG-12, DFCI 05-043, STAMPEDE, and RTOG-0521.
• Patients were stratified as high risk (with 1 risk factor) and very high risk (with 2-3 risk factors and/or cN1).
• The primary outcomes were MFS and OS, and the secondary outcomes included event-free survival (EFS; biochemical failure, locoregional recurrence, and MFS) and prostate cancer-specific mortality.

Results

Baseline Patient Characteristics

• 1,690 patients were analyzed, with nearly two-thirds classified as very high-risk disease.
• The majority of patients had Gleason 8-10 tumors and ECOG performance status 0.
• Median PSA was approximately 20 ng/mL. Less than 10% had clinical-node-positive disease, and nearly all received long-term ADT (except patients in the DFCI 05-042 trial, who received short-term ADT).

Survival Outcomes

• MFS and OS did not improve significantly with the addition of docetaxel, though the hazard ratio was less than 1 (MFS HR: 0.89; OS HR: 0.88); these were not statistically significant.
• Improvements were observed in EFS, and prostate cancer-specific deaths were lower in the docetaxel arm; however, the benefits were modest.
• Greater numerical benefits were observed in the very high-risk subgroup (MFS: HR 0.86; OS: HR 0.85) compared to high-risk disease (MFS HR 0.97; OS: 0.95).

5-Year Survival Outcomes

Survival	High risk		Very high-risk
	RT + ADT	RT + ADT + docetaxel	RT + ADT	RT + ADT + docetaxel
MFS	87 (82-90)	90 (86-93)	74 (71-78)	80 (76-83)
OS	90 (86-93)	93 (90-96)	84 (80-86)	89 (86-92)

 

10-Year Survival Outcomes

Survival	High risk		Very high-risk
	RT + ADT	RT + ADT + docetaxel	RT + ADT	RT + ADT + docetaxel
MFS	67 (61-72)	71 (65-76)	51 (46-55)	55 (49-60)
OS	74 (69-79)	77 (72-82)	62 (57-67)	67 (62-72)

 

Conclusion

The meta-analysis found no statistically significant improvements in MFS and OSA with the addition of docetaxel to radiotherapy and long-term ADT in HRLPC. However, modest benefits were seen in EFS and prostate cancer-related deaths. Future studies may focus on the utilization of biomarker-guided selection of patients who could benefit most from intensified treatment approaches.

Avelumab + Sacituzumab Govitecan (SG) vs Avelumab Monotherapy as First-line (1L) Maintenance Treatment in Patients (pts) with Advanced Urothelial Carcinoma (aUC): Interim Analysis from the JAVELIN Bladder Medley Phase 2 Trial.

Speaker: Jean Hoffman-Censits

Introduction

An interim analysis of the Phase 2 JAVELIN Bladder Medley trial was presented by Dr. Jean Hoffman-Censits from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. The study evaluated avelumab in combination with SG versus avelumab monotherapy as 1L maintenance therapy for patients with aUC who achieved disease control after platinum-based chemotherapy.

Trial Design

The trial was conducted as an international, randomized, open-label Phase 2 study. Eligible patients included those with unresectable locally advanced or metastatic urothelial carcinoma without progression after 4–6 cycles of platinum-based chemotherapy. Patients were randomized in a 1:2:2:2 ratio to receive avelumab monotherapy or avelumab combined with other agents, including SG. The primary endpoints were PFS and safety.

Progression-Free Survival Outcomes

A median PFS of 11.17 months was observed in the avelumab + SG arm, compared to 3.75 months in the avelumab monotherapy arm (including extended control data). The stratified hazard ratio was reported at 0.49, crossing the predefined efficacy boundary. A sensitivity analysis using only randomized patients showed consistent findings, with a median PFS of 3.56 months and a hazard ratio of 0.43.

Overall Survival and Response Rates

Overall survival data were immature at the time of analysis. The median OS was not reached for the combination arm, while it was reported as 23.75 months for monotherapy. Objective response rates were 24.3% for the combination arm versus 2.7% for monotherapy, and disease control rates were 68.9% versus 43.2%, respectively.

Treatment Exposure and Discontinuation

At the data cutoff, 51.4% of patients in the combination arm remained on treatment compared to 27% in the monotherapy arm. Median treatment duration with avelumab was 6.67 months in the combination arm and 3.35 months in the monotherapy arm. SG was administered for a median duration of 5.75 months. The most common reason for treatment discontinuation was disease progression, with 12.2% discontinuing SG due to adverse events.

Safety Findings

Treatment-related adverse events (TRAEs) of any grade were reported in 97.3% of the combination group and 63.9% of the monotherapy group. Grade 3 or higher TRAEs occurred in nearly 70% of patients in the combination arm. Approximately half of the patients in the combination arm required SG dose reductions. A treatment-related death attributed to SG was reported. Common TRAEs in the combination arm included fatigue, diarrhea, asthenia, alopecia, and neutropenia. G-CSF use was noted in around 50% of patients, although this was potentially misstated as occurring in the control arm.

Conclusion

Significant improvement in progression-free survival was demonstrated with avelumab + SG compared to avelumab monotherapy in aUC patients with disease control after platinum-based chemotherapy. Safety findings were consistent with known profiles of both agents, with higher adverse event rates observed in the combination arm.

Exploratory Analysis of Responders from the Phase 3 EV-302 Trial of Enfortumab Vedotin plus Pembrolizumab (EV+P) vs Chemotherapy (Chemo) in Previously Untreated Locally Advanced or Metastatic Urothelial Carcinoma (la/mUC).

Speaker: Shilpa Gupta

Introduction

An exploratory analysis of the Phase 3 EV-302 trial was presented by Dr. Shilpa Gupta from the Cleveland Clinic Taussig Cancer Institute. The trial compared EV+P to chemotherapy as first-line treatment for patients with previously untreated, la/mUC.

Primary Findings

EV + Pwas found to significantly improve survival among patients achieving a complete response (CR) or partial response (PR). The proportion of CRs was observed to be twice as high with EV + Pcompared to chemotherapy. The quality and durability of responses were greater with EV-Pembro, with a 74% probability of maintaining a CR at two years. No new safety signals were identified among responders despite longer treatment durations.

Background of the EV-302 Trial

EV + Pwas established as the global standard of care based on prior analysis showing improved outcomes. Median progression-free survival (PFS) was reported at 12.5 months with EV + P versus 6.3 months with chemotherapy (HR 0.48). Median overall survival (OS) was 33.8 months with EV + Pversus 15.9 months with chemotherapy (HR 0.51). These benefits were observed across all prespecified subgroups, including both cisplatin-eligible and -ineligible patients.

Efficacy in Responders

• ORR: 67.5% with EV + P vs. 44.0% with chemotherapy
• Complete Response (CR): 30.4% vs. 14.5%
• Partial Response (PR): 37.0% vs. 30.0%
  Baseline characteristics of responders in the EV + P arm were found to be consistent with the overall study population.

Duration of Response (DoR)

The median DoR was 23.3 months with EV + P and 7.0 months with chemotherapy. The 24-month response maintenance probability was 50%.

• Cisplatin-Eligible Patients: DoR of 24.4 months (EV + P) vs. 8.3 months (chemotherapy)
• Cisplatin-Ineligible Patients: DoR of 21.9 months vs. 8.8 months

Duration of Complete Response (DoCR)

The median DoCR was not reached with EV + P and was 15.0 months with chemotherapy. A 74.3% probability of maintaining CR at two years was reported with EV + P.

Overall Survival (OS) in Responders

At two years, 76% of responders treated with EV + P were alive (HR 0.59). Among those achieving a CR, 95.4% were alive at two years (HR 0.37).

Safety and Treatment Exposure in Responders

• Treatment Duration: Longer durations were noted in responders. The median number of EV cycles in complete responders was 13 vs. 9 in the overall population. Median combined EV + P cycles were 30 vs. 12.
• Safety Profile: No new safety signals were identified.
• TRAEs of Special Interest: Peripheral neuropathy (EV), rash, hyperglycemia, and ocular toxicities were reported. TRAEs from pembrolizumab were consistent with known data.
• Dose Modifications: 69% of responders had dose modifications, and 53.9% required EV dose reductions. Efficacy was not compromised.

Conclusion

The EV + P combination was confirmed to provide superior and more durable responses in the first-line treatment of la/mUC. The findings were consistent across baseline characteristics and subgroups. Despite longer treatment exposure, the safety profile remained manageable, reaffirming the regimen’s role as a standard of care.

Mitomycin plus BCG as Adjuvant Intravesical Therapy for High-risk, Non–muscle-invasive Bladder Cancer: A Randomized Phase 3 Trial (ANZUP 1301).

Speaker: Dickon Hayne

Introduction

Dr. Dickon Hayne from the University of Western Australia Medical School presented the results of the ANZUP 1301 Phase 3 randomized trial. The trial compared intravesical BCG plus mitomycin to BCG alone in patients with high-risk non-muscle-invasive bladder cancer (NMIBC).

Primary Outcomes

Comparable efficacy was demonstrated between BCG plus mitomycin and BCG alone.

• 24-Month Disease-Free Survival (DFS): 75% with BCG plus mitomycin vs. 71% with BCG alone (HR: 0.87; 95% CI: 0.65–1.16)

Secondary Outcomes

• Complete Response at 3 Months: Achieved in 90% (BCG+mitomycin) vs. 86% (BCG)
• Recurrence-Free Survival at 24 Months: 80% vs. 75% (SHR: 0.85; 95% CI: 0.61–1.19)
• Progression-Free Survival at 24 Months: 92% vs. 90% (SHR: 0.68; 95% CI: 0.41–1.11)
• Overall Survival: Survival curves overlapped; fewer than 10% of patients died during the study

Subgroup Analysis

An exploratory post-hoc subgroup analysis was conducted.

• Greater benefit from BCG plus mitomycin was suggested in patients with higher-risk disease (T1 or CIS)
• Interaction p-value: 0.043

Safety and Adverse Events

• Grade 3 or higher adverse events were rare in both arms
• Serious adverse events included 3 on-treatment deaths (1 MI, 1 sepsis in BCG only arm; 1 mycotic aneurysm in BCG+mitomycin arm)
• Other AEs included myasthenia gravis and an additional mycotic aneurysm in the BCG-only arm

BCG Utilization and Completion

• 40% fewer BCG doses were required in the combination arm
• Completion of ≥75% Planned Doses: 78% (BCG+mitomycin) vs. 68% (BCG)
• Receipt of All Planned Doses: 75% (BCG+mitomycin) vs. 64% (BCG)
• Higher completion rates were observed compared to previous trials

Conclusion

Comparable efficacy and safety were demonstrated between BCG plus mitomycin and BCG alone in the ANZUP 1301 trial. A 40% reduction in BCG dose requirement and higher treatment completion rates were observed with the combination. A potential greater benefit for higher-risk patients was suggested in exploratory analysis. BCG plus mitomycin was presented as a viable alternative to BCG monotherapy, particularly in the context of global BCG shortages.

Nivolumab plus Ipilimumab vs Sunitinib for First-line Treatment of Advanced Renal Cell Carcinoma: Final Analysis from the Phase 3 CheckMate 214 Trial.

Speaker: Robert J. Motzer

Introduction

Dr. Robert J. Motzer presented the final results of the CheckMate 214 trial on behalf of Dr. Tony K. Choueiri and co-investigators. The trial assessed Nivolumab (Nivo) plus Ipilimumab (Ipi) versus sunitinib in first-line advanced clear cell renal cell carcinoma (RCC), with a median follow-up of 9.3 years.

Primary and Secondary Populations

• Primary Analysis: Conducted in intermediate- and poor-risk patients.
• Secondary Analysis: Performed in the intent-to-treat (ITT) population.
• Exploratory Analysis: Included favorable-risk patients.

Efficacy in Intermediate and Poor-Risk Population

• Overall Survival (OS): Sustained benefit shown (HR: 0.69; 95% CI: 0.61–0.81).
• Progression-Free Survival (PFS): 25% remained progression-free at 8 years.
• Duration of Response (DoR): Nearly 50% of responses remained long-term.

Efficacy in Favorable-Risk Population (Exploratory)

• OS: Trend favoring Nivo plus Ipi (HR: 0.80); 13% benefit at 9 years.
• PFS: Favored sunitinib.
• DoR: Responses with Nivo plus Ipi were noted to be more durable.

Efficacy in ITT Population

• OS: Sustained long-term benefit observed (HR: 0.71; 95% CI: 0.64–0.82).
• 42% alive at 6 years
• 31% alive at 9 years
• OS by Subgroups
• Intermediate risk: HR = 0.73
• Poor risk: HR = 0.63
• Sarcomatoid features: HR = 0.53
• PFS: Divergence of curves after 24 months; benefit maintained through 8 years (23%).
• Objective Response Rate (ORR)
• ITT population: 27.5% PR, 12% CR
• Durability of Response
• 60% of responses are ongoing at final analysis
• CR durability in ITT: 80%
• CR durability in intermediate/poor risk: 84%
• Median DoR: 76.2 months
• 50% of responders remained in response at 6 and 8 years

Treatment Exposure and Discontinuation

• Most patients had discontinued study therapy.
• Five patients remained on nivolumab monotherapy.
• More discontinuations due to progression occurred in the sunitinib arm; more due to AEs in the Nivo plus Ipi arm.
• More PD-1 inhibitors were used post-sunitinib; more TKIs post-Nivo plus Ipi.

Safety and Immune-Mediated Adverse Events

• Common immune-mediated AEs involved GI, skin, thyroid, and liver.
• Grade 3/4 events remained ≤7%.
• Corticosteroids (≥40 mg/day) were used in 31% of patients:
• 21% for >14 days
• 11% for >30 days
• No new deaths or safety signals were reported.
• Most immune-related AEs occurred early; rare late-onset events were still observed at 8–9 years.

Conclusion

The final analysis of CheckMate 214 confirmed that Nivolumab plus Ipilimumab continues to provide durable and long-term survival benefits, high complete response rates, and manageable safety in advanced RCC. These findings reinforce the combination as a standard of care, with the additional option of subcutaneous nivolumab for maintenance therapy.

ASCO, May 30 – June 3, 2025, Chicago