It is an exciting time in the development of new treatments for urologic cancers. There have been a number of major changes both in advanced disease and in the perioperative setting over the past year.
Urothelial and Bladder Cancers
In urothelial cancer, at last, we have randomized data supporting personalized therapy. The FGFR inhibitor erdafitinib showed a survival advantage compared with standard chemotherapy in previously treated advanced disease.1 This will drive the development of further personalized approaches in this disease. There has also been significant progress in the first-line setting of advanced urothelial cancer, where the combination of enfortumab vedotin-ejfv and pembrolizumab received accelerated approval by the U.S. Food and Drug Administration (FDA) based on exceptional data from a randomized phase II study.2
Guest Editor
Thomas Powles, MBBS, MRCP, MD
Dr. Powles is Professor of Genitourinary Oncology and Director of Barts Cancer Centre at St. Bartholomew’s Hospital, London, United Kingdom. He is actively involved in the development of biomarkers and novel drug strategies in genitourinary cancers, and his current work focuses on novel adjuvant and neoadjuvant therapies for early bladder and kidney cancers.
Other antibody drug conjugates such as sacituzumab govitecan-hziy are following close behind, and randomized trials in urothelial cancer are awaited.
There have also been further developments in muscle-invasive bladder cancers, with updated circulating tumor DNA (ctDNA) data showing the ongoing prognostic and predictive relevance of this biomarker.3 IMvigor011 is the confirmatory trial, which remains important in defining the role of ctDNA in this stage of disease. Updated data on adjuvant nivolumab in operable, high-risk, muscle-invasive disease continues to show promising disease-free survival.4 This looks most marked in the bladder rather than in upper tract subgroups.
Controversy around the PD-L1 biomarker—a confusing and inconsistent biomarker in urothelial cancer—continues. There are multiple methods of defining positivity, and the biomarker has failed more often that it has succeeded as a predictive biomarker. If we continue to pursue this, it may hinder progress with other more promising biomarkers.
Renal Cell Carcinoma
Recent studies in kidney cancer have contrasted with those in urothelial cancer, in that there have been a series of negative trials that have altered our thinking of the disease. CONTACT-03 explored sequencing the PD-L1 inhibitor atezolizumab after previous immune checkpoint inhibitors and failed to show a benefit.5 The trial randomly assigned patients whose cancer had recently progressed on PD-1–based therapy to cabozantinib with or without atezolizumab. From an efficacy perspective, the trial was completely negative. It is possible that this finding could be a class effect, and different results would have occurred with PD-1 inhibition. However, the results have wider implications. It should halt the practice of sequencing immune checkpoint inhibition after recent disease progression on previous immune checkpoint inhibitor therapy.
This also applies in the postadjuvant setting recently with pembrolizumab. It appears that patients get one good go with immune checkpoint inhibition, and the hope that previous immune checkpoint inhibition therapy will generate immune-responsive tumors seems incorrect. Testing immune checkpoint inhibition in immune checkpoint inhibition–resistant disease may not be the optimal trial setting.
There has been active debate over the comparative merits of first-line nivolumab/ipilimumab and VEGF/PD-1 combination therapy.6 This is largely based around an unproven theory that ipilimumab/nivolumab has better long-term outcome data. It is true that the shape of the ipilimumab/nivolumab Kaplan-Meier curve for overall survival is attractive.7 It’s also true that VEGF/PD-1 combination therapy is good at achieving control of disease and has impressive progression-free survival.8
Cross-trial comparisons are unwise, particularly exploratory endpoints such as duration of response. The more mature overall survival data for the studies have more similarities than differences across these four trials. Overall, VEGF/PD-1 combinations are better at initial control of disease, whereas the ipilimumab/nivolumab combination spares long-term VEGF tyrosine kinase inhibitor toxicity. The rest is largely up for debate, which is an interesting discussion but often unhelpful. We have four great options for patients with first-line renal cancer, so pick one and use it well.
Triplet therapy has also been explored in the first-line setting of advanced intermediate/poor-risk clear cell renal cell carcinoma with cabozantinib, nivolumab, and ipilimumab in the COSMIC-313 randomized phase III study.9 It shows a progression-free survival advantage over the ipilimumab/nivolumab doublet but no clinically meaningful increase in response or complete response at this stage. The overall survival data are not yet mature and have not been reported. The benefits of the triplet were most marked in the IMDC (International Metastatic Renal Cell Carcinoma Database Consortium) intermediate-risk group. However, this is somewhat counteractive in that many believe the poor-risk patients, with aggressive disease, need the “strongest” triplet therapy. This finding, along with the uncertain role of PD-1 therapy in good-risk disease, highlights the shortcomings of our current predictive biomarker approach based on the IMDC classification.
The IMDC classification was successfully designed as a prognostic tool for VEGF-targeted therapy. Its adoption as a predictive marker for ipilimumab/nivolumab seemed sensible at the time, but now it seems premature and potentially counterproductive. The classification is largely based on dynamic blood parameters such as hemoglobin levels. Patients can move across groups with time, and it’s likely that both disease burden as well as tumor biology may influence risk group allocation. Patients with biologically indolent cancers, which present late, may be the in same IMDC group as biologically aggressive cancers that present early. It would be highly coincidental if these groups accurately correlated with immune-responsive biology. A move toward tissue-based biomarker development is attractive.
Another of controversy in clear cell renal cell carcinoma is in the adjuvant setting. There are three recently reported trials.10-12 Initially, KEYNOTE-564 showed a significant disease-free survival signal and an immature trend toward overall survival with adjuvant pembrolizumab. This changed global practice. Subsequently, adjuvant nivolumab and adjuvant ipilimumab/nivolumab both failed to show an efficacy benefit. The cause of these divergent results is not immediately apparent. It is possible that the different mechanism of action of atezolizumab and the toxicity with ipilimumab/nivolumab are responsible for the negative results.
We await further data with adjuvant nivolumab and the final overall survival for pembrolizumab. A large proportion of patients are being overtreated with this unselected approach, and biomarkers to predict relapse are needed. Refining these markers for molecular residual disease is attractive.
Prostate Cancer
PEACE-1 and ARASENS are two large phase III trials exploring triplet therapy in the first-line setting of hormone-sensitive prostate cancer. Both studies explored similar triplets, with androgen-deprivation therapy, abiraterone acetate or darolutamide, and docetaxel.13,14 The comparator was androgen-deprivation therapy and docetaxel. Both studies showed an overall survival advantage and changed practice. Shortcomings of these studies included the lack of androgen-deprivation therapy and the androgen signaling inhibitor alone as a comparator, which many consider to be a better standard of care. The true value of the addition of docetaxel to androgen-deprivation therapy and the androgen signaling inhibitor doublet is unclear. Subset analysis points toward high-volume and synchronous cancers having greater benefit with the triplet.
The radiolabeled small-molecule, lutetium-177–PSMA-617 showed an overall survival benefit in castration-resistant prostate cancer compared with a standard of care (which induced different therapies).15 The control arm and the PSMA PET biomarker created some controversy, but this novel therapy has become a standard of care for pretreated castration-resistant prostate cancer. This is an exciting new mechanism of action.
PARP inhibition has been a major recent development in castration-resistant prostate cancer.16 Several trials have explored these agents in unselected and homologous recombination repair (HRR)-deficient populations, with a significant progression-free survival advantage noted. The HRR-deficient population shows consistent enrichment for a progression-free survival benefit across all studies. However, the most impressive exploratory data appear to be in the BRCA-mutated populations. No significant overall survival signal has been seen, and the addition of PARP inhibition is associated with toxicity. It is likely that different PARP inhibitors do not have identical efficacy, but they have not been directly tested against each other. Regulatory bodies such as the European Medicines Agency and the FDA have been inconsistent in their approvals, which is understandable because of the differences in trial designs and subset analysis. The personalized approach appears attractive when one considers the efficacy and toxicity data in its entirety.
Overall, all three genitourinary cancers have seen changes in systemic therapy in advanced and perioperative disease settings. Further changes are expected in the future, with novel targets and large practice-changing studies being reported.
DISCLOSURE: Dr. Powles has served as a consultant or advisor to Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Mashup, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Seattle Genetics; has received research funding from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Ipsen, Johnson & Johnson, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Seattle Genetics; and has received reimbursement for travel, accommodations, and expenses from AstraZeneca, Ipsen, Merck Sharp & Dohme, Pfizer, and Roche.
REFERENCES
1. Loriot Y, Necchi A, Park SH, et al: Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med 381:338-348, 2019.
2. Hoimes CJ, Flaig TW, Milowsky MI, et al: Enfortumab vedotin plus pembrolizumab in previously untreated advanced urothelial cancer. J Clin Oncol 41:22-31, 2023.
4. Bajorin DF, Witjes JA, Gschwend JE, et al: Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med 384:2102-2114, 2021.
5. Pal SK, Albiges L, Tomczak P, et al: Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): A multicentre, randomised, open-label, phase 3 trial. Lancet 402:185-195, 2023.
7. Motzer RJ, McDermott DF, Escudier B, et al: Conditional survival and long-term efficacy with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma. Cancer 128:2085-2097, 2022.
8. Motzer RJ, Powles T, Burotto M, et al: Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): Long-term follow-up results from an open-label, randomised, phase 3 trial. Lancet Oncol 23:888-898, 2022.
9. Choueiri TK, Powles T, Albiges L, et al; COSMIC-313 Investigators: Cabozantinib plus nivolumab and ipilimumab in renal-cell carcinoma. N Engl J Med 388:1767-1778, 2023.
10. Powles T, Tomczak P, Park SH; KEYNOTE-564 Investigators: Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for clear cell renal cell carcinoma (KEYNOTE-564): 30-month follow-up analysis of a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 23:1133-1144, 2022.
11. Pal SK, Uzzo R, Karam JA, et al: Adjuvant atezolizumab versus placebo for patients with renal cell carcinoma at increased risk of recurrence following resection (IMmotion010): A multicentre, randomised, double-blind, phase 3 trial. Lancet 400:1103-1116, 2022.
12. Motzer RJ, Russo P, Grünwald V, et al: Adjuvant nivolumab plus ipilimumab versus placebo for localised renal cell carcinoma after nephrectomy (CheckMate 914): A double-blind, randomised, phase 3 trial. Lancet 401:821-832, 2023.
13. Fizazi K, Foulon S, Carles J, et al: Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): A multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design. Lancet 399:1695-1707, 2022.
14. Smith MR, Hussain M, Saad F; ARASENS Trial Investigators: Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med 386:1132-1142, 2022.
15. Sartor O, de Bono J, Chi KN; VISION Investigators: Lutetium-177–PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med 385:1091-1103, 2021.
16. Taylor AK, Kosoff D, Emamekhoo H, et al: PARP inhibitors in metastatic prostate cancer. Front Oncol 13:1159557, 2023.
