Introduction

Therapeutic advances in genitourinary (GU) malignancies have progressed rapidly. Prostate cancer has seen multiple combination treatments in upfront metastatic hormone sensitive disease, as well as the addition of PARP inhibitors for castration resistant prostate cancer with homologous recombination repair defects. In urothelial cancer, the advent of antibody drug conjugates and fibroblast growth factor receptor inhibitors have added multiple therapeutic options in the advanced setting, and many are under investigation in the localized setting. In kidney cancer, combination regimens of immune checkpoint inhibitor (IO) with or without vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) have become standard of care, and novel agents such as HIF2a inhibitors hold much promise. We summarize recent therapeutic updates in GU cancers at the ASCO 2023 annual meeting.

Prostate

Several trials highlighting novel treatments under investigation (including PSMA-directed radionuclide therapy, PARP inhibitors, immunotherapy, bispecific antibodies, and CAR T-cells) were featured (Table 1). In addition, further data from two previously published major phase 3 trials (PEACE-1, TALAPRO-2) with potentially practice-changing implications were presented [1, 2].

Table 1 Novel regimens under investigation—prostate cancer highlights from ASCO 2023
Full size table

Late-breaking data from PEACE-1 evaluating the impact of radiotherapy in first-line patients with de novo metastatic castration sensitive prostate cancer (mCSPC) showed a statistically significant increase in the co-primary endpoint of rPFS in patients with low-volume mCSPC who received standard of care (SOC) + abiraterone + radiotherapy compared to SOC + abiraterone (median 7.5 versus 4.4 years, p = 0.02) [15]. There was no statistically significant rPFS benefit when radiotherapy was added to SOC alone. The co-primary endpoint of overall survival (OS) was not statistically significantly improved between the cohorts, although it is difficult to show an OS improvement in this patient population. Secondary endpoints of castration resistance-free survival and time to serious genitourinary events were improved with the addition of radiotherapy to SOC (± abiraterone) in both the low-volume and overall cohorts. Rates of toxicity appeared similar between groups receiving radiotherapy versus those that did not. Overall, these data suggest a role for radiotherapy in combination with systemic treatment (particularly in regimens containing abiraterone) in patients with low-volume de novo mCSPC.

New data from TALAPRO-2 were presented, evaluating enzalutamide + talazoparib versus enzalutamide + placebo as first-line therapy in patients with metastatic castration resistant prostate cancer (mCRPC) in a cohort of patients specifically selected for homologous recombination repair (HRR) gene alterations, including 169 patients from the original TALAPRO-2 cohort and 230 patients enrolled later [16]. The most common HRR gene alterations present were BRCA2 (~ 30–35% of patients) followed by ATM, CDK12, CHEK2 (~ 15–25% each) and BRCA1 (~ 5%). At a median follow-up of ~ 17 months, talazoparib significantly improved the primary endpoint of rPFS compared to placebo (median NR vs. 13.8 months, HR 0.45; 95% CI 0.33–0.81; p < 0.0001). This benefit was greater in patients with a BRCA1/2 alteration (HR 0.20; 95% CI 0.11–0.36; p < 0.0001) as compared to those without (HR 0.72; 95% CI 0.49–1.07; p = 0.10). Although OS trended toward improvement, the data was not yet mature at time of analysis. The primary toxicity noted with the addition of talazoparib was increased cytopenias, particularly grade 3/4 anemia which occurred in ~ 40% of patients on talazoparib and only 4.5% in the placebo group. Dose interruptions (67% versus 37%) and dose reductions (56% vs. 6%) were more common in the talazoparib group compared to placebo, however rates of discontinuation due to adverse events were similar (10% versus 7%). Overall, this update from TALAPRO-2 provides the basis for the FDA approval of first-line therapy for mCRPC with HRR alterations of enzalutamide with talazoparib. This joins the two other FDA approvals in 2023 of niraparib-abiraterone (based on MAGNITUDE) and olaparib-abiraterone (based on PROPEL), both for BRCA1/BRCA2 mutated mCRPC.

Urothelial carcinoma

Antibody drug conjugates (ADC) and fibroblast growth factor receptor (FGFR) inhibitors have improved outcomes in urothelial cancer, and trials combining immunotherapy with both drug classes were presented at ASCO 2023 (Table 2).

Table 2 Novel regimens under investigation—urothelial cancer highlights from ASCO 2023
Full size table

Enfortumab vedotin (EV) was the first ADC that received FDA approval in 2019 for patients with locally advanced or metastatic urothelial carcinoma (mUC) who had previously received IOs and platinum-containing chemotherapy, based on the EV-301 trial [20]. Since its approval, EV has had clear implications in the treatment guidelines as a second or third line option for patients with mUC. EV-103 is a phase 1b/2, open-label, multiple cohort study for mUC, and patients enrolled in cohort A had cisplatin-ineligible mUC treated with EV and pembrolizumab in the first-line setting [17]. The objective response rate was 73.3% (95% CI 58.1–85.4), and the disease control rates were 84.4% (95% CI 70.5–93.5). With prolonged follow-up, progression-free survival of this cohort was 41.4% at 2 years, with median OS at 26.1 months. The treatment-related adverse events were primarily elevated lipase (17.8%), maculopapular rash (11.1%), and fatigue (11.1%). These data set up the EV-302 trial, a randomized phase 3 trial of EV-pembrolizumab compared with standard platinum-based chemotherapy in first-line mUC. EV-pembrolizumab improved OS (mOS 31.5mo vs. 16.1mo, HR 0.47, 95% CI 0.38–0.58, p < 0.00001) as well as PFS (mPFS 12.5mo vs. 6.3mo, HR 0.45, 95% CI 0.38–0.54, p < 0.00001) [21].

Separately, data from TROPHY-U-01 (phase II, open-label, multiple cohort study) led to the approval of sacituzumab govitecan (ADC against trop-2-expressing tumor cells) in patients with mUC refractory to first line platinum-based chemotherapy and IOs [22]. Finally, disitamab vedotin is the newest ADC targeting HER2 that is being studied in phase-II clinical trials RC48, which have positive preliminary results.

A significant percentage of about 10–20% of urothelial carcinomas harbor FGFR alterations. Erdafitinib is a FGFR inhibitor that was studied first in a phase 2 trial and then validated in THOR, a phase 3 randomized controlled trial comparing erdafitinib to the standard of care chemotherapy (docetaxel vs. vinflunine) [18]. Erdafitinib improved OS (median 12.1 vs. 7.8 months), PFS (median 5.6 months vs. 2.7 months), and ORR (45.6% vs. 11.5%) when compared to chemotherapy. Erdafitinib also had fewer serious treatment-related adverse events, 13.3% versus 24.1%, and fewer deaths, 1 versus 6, when compared to the chemotherapy control group. Primary grade 3 or 4 toxicities with erdafitinib were hyperphosphatemia, diarrhea, stomatitis, and palmar-plantar erythrodysesthesia.

Additionally, the Norse phase 2 study by Siefker-Radtke et al. explored the addition of cetrelimab (PD-1 inhibitor) to erdafitinib in the first line setting in patients who are both FGFR mutated and cisplatin ineligible [19]. There was increased ORR of 54.5% at 12 months in the combination group compared to 44.2% in the erdafitinib alone group. The median PFS was 10.97 months in the combination group compared to 5.62 months in the erdafitinib alone arm.

Renal cell carcinoma

In the treatment of clear cell renal carcinoma (ccRCC), there are five first-line doublet options in the treatment naïve and multiple single agent/double options in the refractory setting available. However, the bases for these approved therapies are IO, VEGFR-TKI, and/or mammalian target of rapamycin (mTOR) inhibitor. Additional agents and therapeutic combinations are urgently needed, and ASCO 2023 highlighted several currently under investigation.

The optimal therapeutic option for patients who have progressed on IO therapy has been debated, and the phase III CONTACT-03 trial evaluated cabozantinib 60 mg PO daily (n = 259) with or without atezolizumab 1200 mg IV every 3 weeks (i.e., IO rechallenge, n = 263) in patients with advanced RCC and radiographic progression on or after IO therapy [23, 24]. At a median follow-up of 15.2 months, when comparing atezolizumab-cabozantinib to cabozantinib, no statistically significant differences were observed in the primary endpoints of PFS (median 10.6 vs. 10.8 months, HR 1.02, 95% CI 0.83–1.28, p = 0.78) or OS (median 25.7 months vs. not evaluable, HR 0.94, 95% CI 0.70–1.27, p = 0.69). Increased toxicity was observed in the combination arm, which discourages the sequential use of cabozantinib-atezolizumab immediately after IO progression.

In terms of novel agents, preliminary results from arm B5 of the phase I/II KEYMAKER-U03B study were reported. In the U03B trial, belzutifan 120 mg PO daily (HIF-2a inhibitor) plus lenvatinib 20 mg PO daily was given to 30 patients with advanced ccRCC after progression on IO and VEGFR-TKI [25]. Preliminary efficacy endpoints included ORR of 50% and median PFS of 11.2 months. Toxicities were overall manageable with HTN (27%) and anemia (17%) being the most common grade 3–4 treatment-related adverse events (TRAEs). Additional trials with promising efficacy include a phase II study of batiraxcept (an AXL inhibitor) ± cabozantinib ± nivolumab (ORR 0% for batiraxcept monotherapy, but promising at 36% for batiraxcept with cabozantinib, and 55% for the triplet, respectively) and the phase I/II study of entinostat (histone deacetylase inhibitor) in combination with atezolizumab and bevacizumab (up to ORR of 60% in IO-naïve cohort) [26, 27]. Other notable trials in progress include the phase 1b/2 study of triplet therapy with 177Lu-girentuximab (antibody-radioisotope targeting carbonic anhydrase IX, which is expressed in > 90% of ccRCC tumor cells) combined with cabozantinib and nivolumab, and the phase I/II study of belzutifan with or without palbociclib (CDK 4/6 inhibitor, LITESPARK-024) [28, 29].

Though the therapeutic options for ccRCC have made significant advances, little improvement has been made in the management of non-clear cell renal cell carcinoma (nccRCC), in part due to its rarity and heterogeneity (different tumor types with distinct biological entities). Several recent studies suggest combination regimens with IO/VEGFR-TKI have reasonable efficacy in nccRCC (such as NCT03635892 evaluating cabozantinib plus nivolumab) [30]. An update from the phase II KEYNOTE-B61 (NCT04704219) of lenvatinib 20 mg PO daily and pembrolizumab 400 mg IV every 6 weeks was presented at ASCO 2023 (n = 158, including 59% papillary and 18% chromophobe) [30,31,32,33]. Overall, ORR was achieved in 49% of the patients, with a DCR of 82%, median PFS of 17.9 months, and 75% of the responders retaining their response ≥ 12 months. OS was not reached. Adverse events (AEs) were overall similar to those observed in the phase III CLEAR study with no new safety concern observed [32,33,34]. As such, KEYNOTE-B61 represents the largest trial to investigate IO/VEGFR-TKI combination in patients with previously untreated nccRCC and demonstrates promising antitumor activity of pembrolizumab plus lenvatinib.

Additionally, the interim analysis from the single-arm, phase II trial of the triplet combination, cabozantinib/ipilimumab/nivolumab in treatment naïve patients with nccRCC (CaNI trial, NCT04413123) were presented [35]. 39 patients received treatment, and at a median follow-up of 10.4 months, ORR was 18% with DCR of 76%. Twelve-month PFS was 51% and 12-month OS was 79%. Similar to COSMIC-313, where the same triplet was given in ccRCC, there was significant toxicity (grade 3/4 74% with grade 3/4 liver toxicity of 36%) and therapy discontinuation rate (21%), potentially contributing to the suboptimal efficacy. Thus, there remains a need for alternative dosing of current triplet therapy, or novel, more tolerable, triplet combinations [35, 36].

Conclusion

Many novel therapies across GU malignancies have transformed outcomes for patients with prostate, bladder, and kidney cancers. Targeted treatments and antibody drug conjugates are heralding an era of precision oncology. Optimizing treatment selection and sequencing of therapies remains a challenge as resistance mechanisms are uncovered.