Practice-Changing Studies in Genitourinary Cancers

The annual European Society for Medical Oncology (ESMO) Congress held in October 2023 presented several practice-changing studies in genitourinary cancers. Some of the most remarkable advances presented at the conference pertained to metastatic urothelial carcinoma (mUC). The first-line treatment of mUC typically consists of a platinum-based regimen in eligible patients, followed by immunotherapy maintenance; however, the results of the EV-302 and CheckMate 901 studies may significantly impact first-line treatment recommendations for mUC. EV-302 was a phase 3 trial that compared the combination of enfortumab vedotin-ejfv (EV) and pembrolizumab to gemcitabine with either cisplatin or carboplatin. This combination was previously studied in EV-103, a phase 1b/2 trial that investigated the combination as first-line therapy in cisplatin-ineligible patients. Based on the positive results of this study, the FDA granted an accelerated approval of the combination regimen for patients with cisplatin-ineligible advanced or metastatic urothelial carcinoma.1,2 EV-302 expands on the role of EV and pembrolizumab in mUC by investigating its efficacy head-to-head against standard of care platinum-based chemotherapy. At a median follow-up of 17.2 months, EV and pembrolizumab nearly doubled the progression-free survival (PFS) and overall survival (OS) in comparison to chemotherapy, with a median PFS of 12.5 months compared to 6.3 months, and a median OS of 31.5 months compared to 16.1 months. The combination of EV and pembrolizumab was also associated with a significant increase in overall response rate (ORR) to 67.7%, of which almost 30% of patients had a complete response, in comparison to 44.4% with chemotherapy. The combination was well tolerated, with grade 3 or higher treatment-related adverse events (TRAEs) occurring in 55.9% of patients in comparison to 69.5% of patients who received chemotherapy; the most common TRAEs with EV and pembrolizumab were maculopapular rash (7.7%) hyperglycemia (5%), and neutropenia (4.8%).3

In the same presidential session, results of the CheckMate 901 trial were presented and simultaneously published in the New England Journal of Medicine. This phase 3 trial compared nivolumab in combination with gemcitabine and cisplatin to chemotherapy alone in patients with previously untreated mUC. The trial met its dual primary endpoints of OS and PFS. Median PFS was 7.9 months with the addition of nivolumab, in comparison to 7.6 months with chemotherapy alone; likewise, the addition of nivolumab resulted in a statistically significant improvement in median OS, reported as 21.7 months in comparison to 18.9 months with chemotherapy alone. The addition of nivolumab also improved the rate and duration of responses, with an ORR of 57.6% versus 43.1% and a median duration of response of 37.1 months compared to 13.2 months with chemotherapy alone. Grade 3 or greater TRAEs occurred in 62% of patients who received nivolumab and chemotherapy, in comparison to 52% of patients who received chemotherapy alone.4,5 CheckMate 901 is not the first trial to assess the combination of chemotherapy and immunotherapy in mUC, but it is the first to report positive results. Previously, the IMvigor130 and KEYNOTE-361 studies investigated the addition of atezolizumab and pembrolizumab to chemotherapy and found no benefit; both trials allowed carboplatin to be substituted for cisplatin, and only 30% and 44% of patients received cisplatin in each trial, respectively. One potential suggestion for the positive results of CheckMate 901 is the immunomodulatory effects of cisplatin and its synergy with immunotherapy in comparison to carboplatin.6,7 The results of both the EV-302 and CheckMate 901 are likely to dramatically change the treatment landscape of mUC, although several unanswered questions remain. With the combination of EV and pembrolizumab being used as first-line therapy, optimal second- and subsequent-line therapy is not well understood. With more widespread use of EV and pembrolizumab, clinicians must also be mindful of the unique side effect profiles of EV and pembrolizumab, as well as increased financial toxicity in comparison to chemotherapy.

Notable Renal Cell Carcinoma Trials Presented

There were also notable trials presented at ESMO 2023 in renal cell carcinoma (RCC). Several trials investigating the use of the hypoxia-inducible factor (HIF)-2α inhibitor belzutifan were presented, including the LITESPARK-005 study, which compared belzutifan to everolimus in patients with metastatic clear cell renal cell carcinoma (ccRCC) and progression on at least one anti-PD1 agent and VEGFR inhibitor. Belzutifan is currently FDA approved for the treatment of patients with von Hippel-Lindau (VHL)-associated RCC, where its efficacy has been investigated due to the overexpression of HIF-2α in patients with VHL; however, results of the LITESPARK-005 trial may lead to approval of belzutifan in a wider population of patients with metastatic RCC. This phase 3 trial included a heavily pre-treated population, with approximately 87% of patients having received 2 to 3 prior lines of therapy, and 50% of patients having received 2 to 3 prior tyrosine kinase inhibitors. About 80% of patients had intermediate to poor risk disease based on the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic model. The trial found a statistically significant improvement in PFS and ORR with belzutifan when compared to everolimus. With a median follow-up of 25.7 months, the 18-month PFS was 22.5% versus 9.0%, and the ORR was 22.7% versus 3.5% for belzutifan and everolimus, respectively. The incidence of grade 3 or greater TRAEs was similar in both arms at approximately 62%, with the most common adverse events with belzutifan being anemia and fatigue; however, rates of discontinuation were higher with everolimus, at 15% in comparison to 6%.8 Other notable trials in RCC that were presented at ESMO 2023 included the RENOTORCH and MEDI5752 trials. RENOTORCH was a phase 3 study of toripalimab, a humanized IgG4 monoclonal antibody against programmed death-1 (PD-1), combined with axitinib versus sunitinib for first-line treatment of advanced RCC, which found a significant improvement in PFS for the combination.9 MEDI5752 was a phase I trial that investigated the efficacy of volrustomig as first-line treatment in patients with metastatic RCC. Volrustomig is a novel PD-1/CTLA-4 bispecific monoclonal antibody that achieves full PD-1 blockade with preferential CTLA-4 inhibition on activated PD-1-positive T-cells. The trial found that volrustomig produced an encouraging ORR of 48.4%, which may prompt future trials in RCC.10

Exciting Prostate Cancer Trials Presented

Lastly, there were several exciting trials in prostate cancer presented at ESMO 2023. Results of the ENZA-p trial, which was a phase 2 trial that evaluated the efficacy of 177Lu-PSMA-617 (LuPSMA) in combination with enzalutamide versus enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC) at high risk of progression, were reported. Patients in ENZA-p had not previously been treated with chemotherapy or an androgen receptor pathway inhibitor (ARPI). They were randomly assigned to receive enzalutamide with or without LuPSMA delivered in 2 or 4 doses. The primary endpoint was PSA-progression free survival (PSA-PFS), defined as the interval from randomization until first evidence of PSA progression according to the Prostate Cancer Working Group criteria. Over a median follow-up of 20 months, the PSA-PFS was 13 months with LuPSMA and enzalutamide in comparison to 7.8 months with enzalutamide alone. Radiographic PFS also favored the combination arm. Serious adverse events were reported in 33% of patients who received LuPSMA and enzalutamide, in comparison to 35% of patients who received enzalutamide alone.11,12 The PSMAfore was a phase 3 trial, which investigated the efficacy of LuPSMA in taxane-naïve patients with mCRPC and at least 1 PSMA positive lesion who had progressed on an ARPI. Patients were randomized to receive either LuPSMA for 6 doses or a change in ARPI (abiraterone or enzalutamide). Patients randomized to sequential ARPI could cross over to LuPSMA following radiographic disease progression. At a median follow-up of 7.3 months, the radiographic PFS was 12.0 months with LuPSMA in comparison to 5.6 months with change in ARPI. Furthermore, 57.6% of patients treated with LuPSMA saw at least a 50% decrease in PSA levels, versus 20.4% of patients treated with a change in ARPI. These results are promising and could change the current treatment paradigm for patients with advanced prostate cancer.13,14


1.Hoimes CJ, Flaig TW, Milowsky MI, et al. Enfortumab vedotin plus pembrolizumab in previously untreated advanced urothelial cancer. JCO. 2023;41(1):22-31.

2.FDA grants accelerated approval to enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial carcinoma. Accessed November 21, 2023.

3.Powles TB, et al. EV-302/KEYNOTE-A39: Open-label, randomized phase 3 study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (chemo) in previously untreated locally advanced metastatic urothelial carcinoma (LA/mUC). ESMO Congress 2023, LBA6

4.Van der Heijden MS, et al. Nivolumab plus gemcitabine-cisplatin versus gemcitabine-cisplatin alone for previously untreated unresectable or metastatic urothelial carcinoma: results from the phase 3 CheckMate 901 trial. ESMO Congress 2023, LBA7

5.Van der Heijden MS, Sonpavde G, Powles T, et al. Nivolumab plus gemcitabine–cisplatin in advanced urothelial carcinoma. N Engl J Med. Published online October 22, 2023:NEJMoa2309863.

6.Grande E, Bamias A, Galsky MD, et al. Overall survival (OS) by response to first-line (1l) induction treatment with atezolizumab (Atezo) + platinum/gemcitabine (Plt/gem) vs placebo + plt/gem in patients (Pts) with metastatic urothelial carcinoma (mUC): Updated data from the IMvigor130 OS final analysis. JCO. 2023;41(16_suppl):4503-4503.

7.Powles T, Csőszi T, Özgüroğlu M, et al. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(7):931-945.

8.ESMO 2023: Invited discussant for LITESPARK-003, LITESPARK-005, and LITESPARK-013. Accessed November 21, 2023.

9.ESMO 2023: RENOTORCH: Toripalimab combined with axitinib versus sunitinib in first-line treatment of advanced renal-cell carcinoma: a randomized, open-label, phase 3 study. Accessed November 21, 2023.

10.ESMO 2023: MEDI5752 (Volrustomig), a novel PD-1/CTLA-4 bispecific antibody, in the first-line treatment of 65 patients with advanced clear cell renal cell carcinoma. Accessed November 21, 2023.

11.Emmett L, Subramaniam S, Joshua AM, et al. ENZA-p trial protocol: a randomized phase II trial using prostate-specific membrane antigen as a therapeutic target and prognostic indicator in men with metastatic castration-resistant prostate cancer treated with enzalutamide (ANZUP 1901). BJU Int. 2021;128(5):642-651. doi:10.1111/bju.15491.

12.ESMO 2023: Enzalutamide and 177Lu-PSMA-617 in poor-risk metastatic castration-resistant prostate cancer (mCRPC), a randomized, phase 2 trial. Accessed November 21, 2023.

13.Sartor O, Gauna DC, Herrmann K, et al. LBA13 Phase III trial of [177Lu] Lu-PSMA-617 in taxane-naive patients with metastatic castration-resistant prostate cancer (PSMAfore). Annals of Oncology. 2023;34:S1324-5.

14.Sartor O, et al. Phase 3 trial of [177Lu]Lu-PSMA-617 in taxane-naive patients with metastatic castration-resistant prostate cancer (PSMAfore). ESMO Congress 2023, LBA13.

Christine Barrett

Christine Barrett

PharmD, BCOP

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