As noted above, the combined ICIs (nivolumab and ipilimumab) and the combinations of an ICI and a TKI (pembrolizumab plus axitinib, avelumab plus axitinib) are currently mainstream as first-line therapy for metastatic RCC (10–12). These combinations all demonstrated superior efficacy to sunitinib with a tolerable safety profile in the phase III CheckMate-214, Keynote-426, and Javelin Renal 101 clinical trials, respectively (9–11)

Currently, there is no validated recommendation to select the first-line therapy among these three regimens although the combination of nivolumab and ipilimumab is approved only for the International mRCC Database Consortium (IMDC) intermediate/poor category. Numerically, nivolumab plus ipilimumab had a higher complete response (CR) rate (9%) than the ICI plus TKI regimens (5.8% for pembrolizumab and axitinib and 4.4% for avelumab plus axitinib) (9–11). In the sub-analysis of CheckMate-214, which consisted of 139 patients with intermediate- and poor-risk sarcomatoid RCC (28), nivolumab plus ipilimumab compared to sunitinib demonstrated a higher median overall survival (OS; not reached vs 14.2 months), progression-free survival (PFS; 26.5 months vs 5.1 months), and objective response rate (ORR; 60.8% vs 23.1%) (28). It is particularly noteworthy that this combination achieved the highest CR rates ever (19%) for metastatic RCC patients with sarcomatoid component (28). On the other hand, in this combination therapy, 28% of patients either had progressive disease (PD) as the best response or were not evaluable, compared to ~16% for pembrolizumab plus axitinib and ~15% for avelumab plus axitinib (9–11). These are smaller percentages than with nivolumab plus ipilimumab therapy. When prompt disease control is necessary due to rapidly symptomatic progressive disease, a combination of ICI and TKI may be the preferred strategy (29, 30).

The METERO trial is the randomized, open-label, phase III clinical trial (n = 658) that compared the efficacy of cabozantinib with everolimus in patients with metastatic RCC who had progressed after TKI therapy (12). The median PFS (7.4 vs 3.8 months, HR 0.58, P < 0.001), OS (HR 0.67, P = 0.005), and ORR (21% vs 5%, P < 0.001) were higher for patients treated with cabozantinib than everolimus (12). In addition, the CABOSUN trial is a randomized phase II multicenter trial that compared cabozantinib with sunitinib as first-line therapy in patients with treatment-naïve metastatic RCC (n = 157, IMDC intermediate/poor category) (13). The median PFS (8.2 vs 5.6 months, HR 0.66, P = 0.012), ORR (33% vs 12%), and disease control rate (DCR: 75% vs 47%) were higher for patients treated with cabozantinib than sunitinib (13). Cabozantinib is the first agent that demonstrated greater efficacy than sunitinib for the treatment-naïve metastatic RCC patients. Therefore, cabozantinib is currently considered as one of the standard options for second-line treatment after not only the ICI/TKI but also the ICI/ICI combination therapies, and as an alternative first-line therapy for those patients who are ineligible for ICI therapy.

The Checkmate 9ER is the phase III open-label randomized clinical trial (n=651) for previously untreated metastatic RCC (28). The median PFS, the probability OS at 12 months, and the ORR of the patients treated with nivolumab plus cabozantinib vs sunitinib were 16.6 months vs 8.3 months (HR 0.51, P < 0.001), 85.7% vs 75.6% (HR 0.60, P = 0.001), and 55.7% vs 27.1% (P < 0.001), respectively (14). Grade 3 or higher AEs for any cause were 75.3% for nivolumab plus cabozantinib vs 70.6% for sunitinib (14). In addition, patients reported better health-related quality of life with nivolumab plus cabozantinib than with sunitinib (14).

Lenvatinib, another anti-angiogenesis agent, acts as a multiple kinase inhibitor against the VEGFR1, VEGFR2, and VEGFR3 (15). The combination of lenvatinib and pembrolizumab demonstrated superior efficacy to sunitinib in the phase III international clinical (the CLEAR) trial (15). In this trial, a total of 1069 patients were randomly assigned to receive lenvatinib plus pembrolizumab (n = 355), lenvatinib plus everolimus (n = 357), or sunitinib (n = 357) (15). The median PFS and OS periods were longer with lenvatinib plus pembrolizumab than with sunitinib (median PFS: 23.9 vs 9.2 months, HR 0.39, P < 0.001, OS: HR 0.66, P = 0.005, respectively) (15). Grade 3 or higher adverse events emerged or worsened during treatment in 82.4% of the patients who received lenvatinib plus pembrolizumab; those in at least 10% of the patients in this group included hypertension, diarrhea, and elevated lipase levels (15).

Nivolumab plus cabozantinib and pembrolizumab plus lenvatinib are the third and fourth ICI-plus-TKI combination therapies for metastatic RCC.

Keynote-564 is a phase III, double-blind, multicenter trial of pembrolizumab vs placebo following nephrectomy in patients with high-risk clear cell RCC (16). High-risk criteria included pT3, pT4, or any N+ disease. In the pT2 cases, tumors with Fuhrman Grade 4 or sarcomatoid component included were considered to be high-risk (16). The high-risk category also included having no evidence of disease after resection of oligometastatic sites ≤ 1 year from nephrectomy. Adjuvant pembrolizumab after nephrectomy demonstrated a statistically significant increase in disease free survival (DFS: primary endpoint) compared with placebo (HR 0.68, P = 0.001) (16). The DFS rates for pembrolizumab vs placebo were 85.7% vs 76.2% at 12 months and 77.3% vs 68.1% at 24 months (16). Safety results were in line with expectations, and there was low incidence (7.4%) of high-dose corticosteroid treatment for immune-related AEs (16). The investigators concluded that adjuvant pembrolizumab will be a potential new standard of care for the patients with high-risk RCC after the radical surgery, although additional follow-up is planned for the key secondary endpoint of OS (16).

The schematic standard of care for medical treatment of metastatic RCC in 2022 is depicted in Figure 1A . As first-line therapy, there are five optional combination therapies (nivolumab plus ipilimumab, pembrolizumab plus axitinib, avelumab plus axitinib, nivolumab plus cabozantinib, and pembrolizumab plus lenvatinib; however, nivolumab plus ipilimumab therapy is approved only for the IMDC intermediate/poor category). Because there is currently no validated recommendation to select first-line therapy, biomarkers to predict the response and prognosis are vitally important. As second-line therapy, cabozantinib and axitinib will often be chosen following pembrolizumab plus axitinib, avelumab plus axitinib, or nivolumab plus cabozantinib. For the patients treated with nivolumab plus ipilimumab or pembrolizumab plus lenvatinib, both cabozantinib and axitinib are candidates. The representative clinical trials for metastatic RCC are shown in Table 2 .

Javelin Bladder 100 was a phase III open-label clinical trial for patients with unresectable locally advanced or metastatic urothelial cancer who did not have disease progression with first-line chemotherapy (four to six cycles of GC or gemcitabine plus carboplatin) to receive maintenance avelumab plus best supporting care (BSC) or BSC alone (17). The median OS and the OS at 1 year were significantly better when treated with the avelumab plus BSC than with BSC alone (21.4 months, 71.3% vs 14.3 months, 58.4%, HR 0.69, P = 0.001). The median PFS for avelumab plus BSC was also longer than that of BSC alone (3.7 vs 2.0 months, HR 0.62, 95% confidence interval [CI]: 0.52-0.75) (17). The incidence of adverse events of Grade 3 or higher was 47.4% with avelumab plus BSC vs 25.2% with BSC alone. Maintenance avelumab therapy is a current standard of care for patients who have responded to the first-line GC [CR, PR, or stable disease (SD)] (17).

The EV-301 clinical trial is a global, open-label, randomized phase III clinical trial of enfortumab vedotin for the treatment of metastatic UC patients who had previously received both platinum-containing and ICI therapies. The control arm consisted of investigator-chosen chemotherapy (docetaxel, paclitaxel, or vinflunine) (8). The median PFS and OS for the enfortumab vedotin group (n = 301) were longer than for the chemotherapy group (n = 307) (PFS: 5.55 vs 3.71 months, HR: 0.62, P < 0.001; OS: 12.88 vs 8.97 months, HR: 0.70, P = 0.001). Regarding the safety profile, the incidence of events of Grade 3 or higher was similar in the two groups (51.4% and 49.8%, respectively) (8). Grade 3 or higher treatment-related adverse events that occurred in at least 5% of patients receiving enfortumab vedotin included maculopapular rash (7.4%), fatigue (6.4%), and decreased neutrophil count (6.1%) (8). Because of the excellent efficacy and the controllable safety profile, enfortumab vedotin represents an important novel therapeutic strategy as third-line therapy for patients who experienced both platinum-containing and immune checkpoint inhibitor therapies.

In addition, there are two agents, which were recently granted accelerated approval by the United States Food and Drug Administration (FDA). One is erdafitinib, which is a tyrosine kinase inhibitor of fibroblast growth factor receptor (FGFR) 1-4 (34). Erdafitinib demonstrated antitumor activity in an open-label, phase II study, which enrolled patients with metastatic UC (n=99), who had FGFR mutations (34). In this phase II study, the confirmed ORR, and the median PFS and OS periods were 40% (CR: 3%, PR: 37%), 5.5 months, 13.8 months, respectively (34) Among the 22 patients who had undergone previous immunotherapy, the ORR was 59% (34). Treatment-related AEs of grade 3 or higher were reported in 46% of the patients and almost all were managed by dose reduction (34). No treatment-related death was reported.

Another agent is sacituzumab govitecan. Sacituzumab govitecan is a new ADC and a monoclonal antibody specific for Trop-2 conjugated with SN-38, which is the active metabolite of irinotecan (35). The TROPHY-U-01 trial is a multicohort, open-label, phase II study. In this clinical trial, cohort 1 included patients (n=113) with locally advanced or unresectable or metastatic UC who had progressed after prior platinum-based combination chemotherapy and checkpoint inhibitors (35). At a median follow-up of 9.1 months, the ORR, the median PFS and the median OS periods were 27%, 5.4 months, and 10.9 months, respectively (35). Regarding grade ≥ 3 adverse events, neutropenia (35%), leukopenia (18%), anemia (14%), diarrhea (10%), and febrile neutropenia (10%) were seen and 6% discontinued due to treatment-related AEs (35). The respective confirmatory clinical trials are currently underway.

To date, various clinical trials using enfortumab vedotin as first-line therapy for metastatic urothelial cancer have been conducted. Among them, high response rates were reported using enfortumab vedotin in combination with pembrolizumab as first-line treatment for metastatic disease (8). The CR, OR, and DCR rates were 13%, 71%, and 93%, respectively. The phase III EV-302 clinical trial, which randomizes patients with treatment naive metastatic urothelial cancer to the combination of enfortumab vedotin and pembrolizumab or to the standard of care platinum-based chemotherapy, is ongoing (8, 32, 33).

CheckMate 274 is a phase III, randomized, double-blind, multicenter study of adjuvant nivolumab vs placebo in patients with high-risk MIUC (18). In this study, the high-risk patients were those with ypT2-ypT4a or ypN+ MIUC who had neoadjuvant cisplatin chemotherapy and those with pT3-pT4a or pN+ MIUC without prior neoadjuvant cisplatin chemotherapy. The planned therapy started within 120 days after radical surgery. Primary endpoints were DFS in the intent-to-treat (ITT) population and DFS in the patients with tumor PD-L1 ≥ 1%. Stratification factors were PD-L1 status (<1% vs ≥ 1%), presence and absence of prior neoadjuvant cisplatin-based chemotherapy, and nodal status (+ vs -). Adjuvant therapy was performed for up to 1 year. Among the ITT population, the median DFS period of the nivolumab group was significantly longer than that of the placebo group (21.0 vs 10.9 months, HR: 0.70, P < 0.001) (18). Regarding the PD-L1 ≥ 1% patients, the median DFS for the nivolumab group was also longer (not reached vs 10.8 months, HR: 0.53, P <0.001). The safety and tolerability of nivolumab monotherapy was consistent with previous reports in other tumor types, including in patients with metastatic UC (18). In addition, no deterioration in health-related quality of life was observed with nivolumab vs placebo (18). Based on these excellent results, approval of adjuvant nivolumab after radical surgery is anticipated in clinical practice.

A schematic standard of care for treatment of metastatic UC in 2022 is shown in Figure 1B . The GC regimen, pembrolizumab, and enfortumab vedotin are recommended as the first-, the second-, and the third-line agents, respectively. Because there are various ongoing clinical trials that can reveal the next generation standard of care ( Table 2 ), the standard medical treatment of the metastatic UC has been and will continue to be changing year by year.

The United States Food and Drug Administration (US FDA) approval of pembrolizumab for the treatment of metastatic solid tumors in patients with MSI-high was based on the excellent results in five single-arm clinical trials, Keynote-12, -28, -16, -158, and -164 (45, 46). The ORR was 39.6% (95% CI: 31.7-47.9) with a 7% CR rate among 149 heavily treated patients with 15 different tumor types, including a single CRPC patient (19). The duration of response ranged from 1.6 to 22.7 months, with 78% of responses lasting ≥ 6 months (19). The adverse event profiles of pembrolizumab were similar to those observed across prior trials in other indications (19). This approval is the first time that the FDA has approved a cancer treatment for an indication based on a common biomarker, regardless of the primary site. Previously, we reported a first Japanese CRPC case that demonstrated clinical benefit from pembrolizumab treatment (47). The rarity of MSI-high tumors in CRPC may hamper pembrolizumab administration. This potentially active agent, however, should be considered as part of a treatment regimen for patients with MSI-high CRPC.

The PROfound trial is a prospective phase III trial for the patients with metastatic CRPC who had disease progression while receiving an ARAT agent (enzalutamide or abiraterone) (6). All patients had a qualifying alteration in prespecified genes with a direct or indirect role in homologous recombination repair (HRR) and were randomly assigned to receive the PARP inhibitor olaparib or the ARAT agents enzalutamide or abiraterone (control group) (6). The median radiological PFS in patients with alterations in BRCA1, BRCA2, or ATM (the primary endpoint) was significantly longer in the olaparib group than in the control group (7.4 vs 3.6 months, HR: 0.34, P < 0.001) (47). A significant benefit was also observed with respect to the confirmed ORR (33% vs 2%, HR: 20.86, P < 0.001) and the time to pain progression (HR: 0.44, P = 0.02) (6). Although 81% of the patients in the control group who had progression crossed over to receive olaparib, the median OS in the patients with alterations in BRCA1, BRCA2, or ATM in the olaparib group was longer than in the control group (18.5 vs 15.1 months, HR: 0.64, P = 0.02) (6). The safety profile in patients who received olaparib was manageable, and anemia and nausea were the main toxic effects (6). Because the exploratory analyses suggested that patients harboring BRCA1 or BRCA2 alterations derived the most benefit, olaparib was approved for the treatment of metastatic CRPC harboring BRCA1/2 mutation in Japan.

The schematic standard of care for the medical treatment of metastatic prostate cancer in 2022 is depicted in Figure 1C . As first-line therapy, there are three optional hormone therapies with ADT, which include abiraterone acetate, enzalutamide, and apalutamide, although an abiraterone acetate therapy is approved only for the LATITUDE high-risk category (46). In addition, due to the positive results of the CHAARTED trial, docetaxel therapy for patients with metastatic HSPC has just been formally approved in Japan (49). When progression during the first-line therapy is seen, it is necessary to confirm the presence or absence of a BRCA1/2 mutation. If a BRCA1/2 mutation is found, the patient should be treated with olaparib. If not, docetaxel chemotherapy should be considered for patients with a good performance status. As third-line or later therapies, the ARAT agents (including abiraterone acetate and enzalutamide), the chemotherapeutic agent cabazitaxel, radium-223, and pembrolizumab (MSI-high) are awaited.