New findings from phase 3 trials presented at the ASCO Annual Meeting 2023 have the potential to influence the clinical management of genitourinary cancers and perhaps establish new standards of care.

Results from the VESPER trial showed that dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) prolongs overall survival (OS) when compared with gemcitabine and cisplatin (GC) as neoadjuvant therapy for muscle-invasive bladder cancer (MIBC).1

Results from the PEACE-1 trial showed that adding prostate radiotherapy (RT) to intensified systemic treatment improves OS in patients with de novo, low-volume metastatic castration-sensitive prostate cancer (mCSPC).2

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Results from the TALAPRO-2 trial showed that adding talazoparib to first-line treatment with enzalutamide improves radiographic progression-free survival (rPFS) in patients with metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) gene alterations.3

And results from the CONTACT-03 trial suggest that rechallenge with an immune checkpoint inhibitor (ICI) provides no benefit for patients with advanced renal cell carcinoma (RCC).4

VESPER: ddMVAC Outperforms GC in MBIC

The VESPER trial “is really a milestone in the history of chemotherapy for MIBC,” lead investigator Christian Pfister, MD, PhD, of Rouen University Hospital in France, said in an interview. “VESPER data confirmed the indisputable superiority of dd-MVAC over GC as neoadjuvant chemotherapy.”

The VESPER trial ( Identifier: NCT01812369) included 500 MIBC patients — 437 who received neoadjuvant chemotherapy and 56 who received adjuvant chemotherapy.

In the neoadjuvant group, 218 patients were randomly assigned to receive dd-MVAC and 219 to receive GC. In the adjuvant group, 30 patients were randomly assigned to dd-MVAC and 26 to GC. Patients received 4 cycles of GC or 6 cycles of dd-MVAC.

For the neoadjuvant and adjuvant cohorts together, the 5-year OS rate was not significantly higher in patients who received dd-MVAC than in those who received GC — 64% and 56%, respectively (hazard ratio [HR], 0.77; 95% CI, 0.58-1.03; P =.078).

In the neoadjuvant group alone, however, the 5-year OS rate was 66% in the dd-MVAC group and 57% in the GC group. Compared with the GC recipients, the dd-MVAC group had a significant 29% decrease in the risk of death (HR, 0.71; 95% CI, 0.52-0.97; P =.032).

On multivariate analysis accounting for tumor stage at randomization, creatinine clearance at baseline, lymph node involvement, and patient status, neoadjuvant dd-MVAC was associated with a 30% decrease in the risk of death (HR, 0.70; 95% CI, 0.51-0.96; P =.028) compared with neoadjuvant GC.

On the other hand, multivariate analysis showed no significant difference in the risk of death between the treatments when used in the adjuvant setting (HR, 1.90; 95% CI, 0.86-4.22; P =.11). Dr Pfister noted, however, that the results for the adjuvant chemotherapy group are not conclusive, as it included only 56 patients.

Dr Pfister also reported that dd-MVAC prolonged disease-specific survival (DSS). For the study population as a whole, the 5-year DSS rate was 72% in the dd-MVAC group and 59% in the GC group. The dd-MVAC recipients had a 37% lower risk of dying from bladder cancer compared with the GC group (HR, 0.63; 95% CI, 0.46-0.86; P = .004).

In the neoadjuvant chemotherapy group, the 5-year DSS rates were 75% and 60% for the dd-MVAC and GC arms, respectively. There was a 44% lower risk of dying from bladder cancer in the dd-MVAC recipients than in the GC recipients (HR, 0.56; 95% CI, 0.39-0.80; P = .001).

VESPER “is a successful pivotal trial that could change the oncologic paradigm in bladder cancer both in daily practice and in future clinical research,” Dr Pfister said.

“Tomorrow, the challenge will be to determine the best therapeutic option in the perioperative setting: chemotherapy combined with immunotherapy, or immunotherapy for all the patients; or better, personalized treatment with a combined approach according to tumor profiling.”

“This study is practice-changing,” said Marijo Bilusic, MD, PhD, of the University of Miami Heath System in Florida, who was not involved in this study. “Until now, oncologists have been offering 3 or 4 cycles of cisplatin-based neoadjuvant therapy, and, from now on, we will try to deliver up to 6 cycles in patients who can tolerate it.”

Dr Bilusic observed that, despite strong OS evidence for the benefit of neoadjuvant chemotherapy, it remains underutilized, with only 20% to 30% of patients receiving this intervention. Although the best treatment option is not defined, dd-MVAC and GC are the most commonly used regimens.

Dr Bilusic predicted that, in light of the VESPER findings, dd-MVAC is probably going to be used more because it offers a shorter duration of neoadjuvant chemotherapy (a cycle is given every 2 weeks compared with every 3 weeks for GC). Patients can undergo radical cystectomy sooner, which is especially important in patients who do not respond to neoadjuvant chemotherapy, Dr Bilusic said.

He pointed out that the trial did not compare 6 cycles of both regimens, so it is hard to conclude that one regimen is better than another since the total dose of cisplatin was 50% higher in the dd-MVAC arm.

“The main finding of the trial is the importance of total cumulative cisplatin dose, as patients who received more than 4 cycles of chemotherapy had better survival than those who received 4 cycles or less. We can conclude that more cisplatin is needed for improved survival,” Dr Bilusic said.

He did note, however, that dd-MVAC was more toxic than GC, and only 60% of patients completed all 6 planned cycles.

This article originally appeared on Cancer Therapy Advisor