Landmark changes in the treatment of genitourinary cancers have occurred over the past year, as summarized in this year’s Genitourinary Oncology Almanac from The ASCO Post. Starting with our area of focus, metastatic renal cell carcinoma, the saga continues with two more positive phase III trials assessing the combinations of targeted therapy with immunotherapy. The CheckMate 9ER study compared the combination of cabozantinib with nivolumab to sunitinib and showed improvements in progression-free survival, response rate, and overall survival in patients with treatment-naive metastatic RCC.¹ Not long after, the CLEAR trial—comparing lenvatinib plus pembrolizumab, lenvatinib plus everolimus, and sunitinib—demonstrated improvement in the same endpoints for the comparison of lenvatinib plus pembrolizumab to sunitinib.² However, one distinguishing characteristic was revealed with recent data from the CheckMate 9ER study at the 2021 Genitourinary Cancers Symposium, which showed an improvement in quality of life with the combination of cabozantinib plus nivolumab.³ This feature makes cabozantinib plus nivolumab the authors’ preferred regimen for front-line therapy of metastatic RCC.

Dramatic progress has also been made in the context of non–clear cell RCC. For years, there was a paucity of randomized data in this setting; those studies that were done included a hodgepodge of different subtypes leading to uninterpretable results. The randomized, phase II SWOG 1500 study compared sunitinib, cabozantinib, savolitinib, and crizotinib. The study showed a meaningful improvement in progression-free survival with cabozantinib vs sunitinib, meeting the primary endpoint and making cabozantinib the standard of care in this disease. Interestingly, the pure MET inhibitors evaluated in this study (savolitinib and crizotinib), while having a strong biologic rationale to work in this setting, failed to show any improvement in progression-free survival relative to sunitinib; these arms of the study were terminated early. ⁴

GUEST EDITOR

Sumanta K. Pal, MD

Dr. Pal is Clinical Professor in the Department of Medical Oncology & Therapeutics Research and Co-Director of the Kidney Cancer Program at City of Hope. He is an internationally recognized leader in the area of genitourinary cancers, including kidney, bladder, and prostate cancer.

Advances in Metastatic Urothelial Cancer

Metastatic urothelial cancer is another area that has seen dramatic changes in the treatment landscape based on results presented over this past year. Perhaps the most unambiguous results come from the EV-301 trial, comparing the nectin-4–targeting antibody-drug conjugate enfortumab vedotin to standard chemotherapy in platinum-refractory metastatic urothelial cancer. The study showed clear evidence of a benefit in overall survival in this setting (the primary endpoint of the study), and also showed impressive gains in progression-free survival and response rate. Although there are notable toxicities associated with enfortumab vedotin (eg, rash and neuropathy), in our experience, the drug appears to be well tolerated compared to chemotherapy and represents a tremendous treatment advance.⁵ There are tempting data from trials combining enfortumab vedotin with checkpoint inhibitors, and these combination regimens are being evaluated in the front-line setting currently.

Over this past year, data have also emerged to further support use of avelumab as maintenance therapy in metastatic urothelial cancer. Data from the JAVELIN Bladder 100 study comparing maintenance avelumab to placebo in patients who had completed four to six cycles of platinum-based chemotherapy for metastatic urothelial cancer were first presented at the 2020 ASCO Annual Meeting.⁶ Bolstering the use of this strategy in clinical practice were subset analyses presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020 suggesting that the benefit is maintained over subgroups divided by PD-L1 status, number of cycles of chemotherapy, and other clinically relevant characteristics.⁷ With several combination studies of chemotherapy with immunotherapy failing to meet the bar in metastatic urothelial cancer (eg, KEYNOTE-361, IMvigor130), it is likely that platinum-based chemotherapy followed by avelumab will remain the standard for the foreseeable future.^8,9

Luis Meza, MD

Zeynep B. Zengin, MD

Adjuvant Therapy for Urothelial Cancer an Ongoing Question

Perhaps the most controversial data for urothelial cancer are found within the adjuvant space. Results of the phase III CheckMate 274 clinical trial were presented at the 2021 Genitourinary Cancers Symposium. This randomized, phase III trial compared nivolumab to placebo in patients with high-risk localized urothelial cancer following surgical resection. The study demonstrated a significant benefit in disease-free survival, but at this time, there are no overall survival data reported.¹⁰ The results of this study contrast starkly with previously published results from IMvigor010, an adjuvant study comparing atezolizumab to observation in a similar disease space. This study was flatly negative, with no difference in disease-free survival or overall survival.¹¹

What then is the standard for adjuvant therapy of urothelial cancer? There are several pivotal trials that may address this question. The phase III AMBASSADOR study (NCT03244384) comparing pembrolizumab to observation is ongoing; this third adjuvant study in a similar disease space may serve as a “tie-breaker” between the CheckMate 274 and IMvigor010 studies. Also, in the adjuvant space, the concept of evaluating biomarkers has gone past simply a cliché: there are now two ongoing studies that will evaluate therapies on the basis of the presence or absence of relevant biomarkers. The IMvigor011 study (NCT04660344) will evaluate atezolizumab adjuvant therapy in patients who have high circulating tumor DNA levels, as detected by an ultrasensitive test. A study being led by the authors, PROOF302 (NCT04197986), will compare infigratinib (a potent and specific FGFR3 inhibitor) to placebo in patients bearing FGFR3 mutation. The latter study is of particular importance, given that the CheckMate 274 data appear to show lesser efficacy with adjuvant nivolumab in patients with upper-tract disease—a setting in which FGFR3 mutation is more abundant.

Radiopharmaceuticals in Metastatic Castration-Resistant Prostate Cancer

In prostate cancer, the research community (as well as the patient community) is waiting with bated breath for the results of the phase III VISION trial comparing lutetium-177–labeled PSMA-617 (LuPSMA) to standard of care in patients with metastatic castration-resistant prostate cancer. A positive result has been announced in press release already; it is likely that these results will be available soon.¹² This result may have been forecast on the basis of compelling data from the ANZUP-led TheraP trial presented at the 2021 Genitourinary Cancers Symposium evaluating, in a randomized phase II design, LuPSMA vs cabazitaxel in metastatic castration-resistant prostate cancer. This study showed a substantial clinical benefit with the former.¹³ Radiopharmaceuticals have already entered the vernacular of oncologists with agents such as radium-223, and LuPSMA, which will represent a welcome addition to the armamentarium.

In metastatic castration resistant prostate cancer, therehave also been further data to support a precision medicine-based approach. We have previously seen clinical benefit with olaparib in patients with metastatic castration resistant prostate cancer bearing DNA repair alterations; over this past year, we have also seen data emerge to suggest an overall survival benefit in patients with BRCA1/2 alterations.¹⁴ These data are welcome in a disease where just 15 years ago the only available therapy was docetaxel.

In summary, the past 12 months have been nothing short of a banner year for genitourinary cancers research. As it must be challenging for the medical oncologist to keep up with the rapid pace of developments in this field, we hope that this Genitourinary Oncology Almanac will serve as a useful “highlights reel.” The articles herein offer a useful narrative incorporating both the data itself and expert opinions from investigators who are intimately involved in the associated research.

DISCLOSURES: Drs. Meza and Zengin reported no potential conflicts of interest. Dr. Pal has served in a consulting or advisory role for Astellas Pharma, Aveo, Bristol Myers Squibb, Eisai, Exelixis, Genentech, GlaxoSmithKline, Ipsen, Myraid Pharmaceuticals, Novartis, Pfizer, and Roche; has received honoraria from Astellas Pharma, Medivation, and Novartis; and has received research funding from Aveo, Bristol Myers Squibb, Eisai, Exelixis, Nektar Therapeutics, Pfizer, and QED.

Dr. Pal is Clinical Professor in the Department of Medical Oncology & Therapeutics Research and Co-Director of the Kidney Cancer Program at City of Hope. Drs. Meza and Zengin are postdoctoral fellows in the Department of Medical Oncology & Experimental Therapeutics at City of Hope.

REFERENCES

1. Choueiri TK, Powles T, Burotto M, et al: 696O_PR: Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: First results from the randomized phase III CheckMate 9ER trial. Ann Oncol 31(suppl 4):S1159, 2020.

2. Motzer R, Alekseev B, Rha S-Y, et al: Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med 2021. February 13, 2021 (early release online).

3. Cella D, Choueiri TK, Blum SI, et al: Patient-reported outcomes of patients with advanced renal cell carcinoma treated with first-line nivolumab plus cabozantinib versus sunitinib: The CheckMate 9ER trial. 2021 Genitourinary Cancers Symposium. Abstract 285. Presented February 13, 2021.

4. Pal SK, Tangen C, Thompson IM, et al: Sunitinib versus cabozantinib, crizotinib, or savolitinib in metastatic papillary renal cell carcinoma: Results from the randomized phase II SWOG 1500 study. 2021 Genitourinary Cancers Symposium. Abstract 270. Presented February 13, 2021.

5. Powles T, Rosenberg JE, Sonpavde G, et al: Primary results of EV-301: A phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated locally advanced or metastatic urothelial carcinoma. 2021 Genitourinary Cancers Symposium. Abstract 393. Presented February 12, 2021.

6. Powles T, et al: Maintenance avelumab + best supportive care (BSC) vs BSC alone after platinum-based first-line chemotherapy in advanced urothelial carcinoma. ASCO20 Virtual Scientific Program. Abstract LBA1.

7. Grivas P, Park S, Voog E, et al: Avelumab first-line (1L) maintenance + best supportive care (BSC) vs BSC alone with 1L chemotherapy for advanced urothelial carcinoma: Subgroup analyses from JAVELIN Bladder 100. ESMO Virtual Congress 2020. Abstract 704MO. Presented September 18, 2020.

8. Alva A, Csöszi T, Ozguroglu M, et al: Pembrolizumab combined with chemotherapy (C) vs C alone as first-line therapy for advanced urothelial carcinoma: KEYNOTE-361. ESMO Virtual Meeting 2020. Abstract LBA23. Presented September 19, 2020.

9. Galsky MD, Arija JAA, Bamias A, et al: Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): A multicentre, randomised, placebo-controlled phase III trial. Lancet 395:1547-1557, 2020.

10. Bajorin DF, Witjes JA, Gschwend J, et al: First results from the phase 3 CheckMate 274 trial of adjuvant nivolumab vs placebo in patients who underwent radical surgery for high-risk muscle-invasive urothelial carcinoma (MIUC). 2021 Genitourinary Cancers Symposium. Abstract 391. Presented February 12, 2021.

11. Hussain MHA, Powles T, Albers P, et al: IMvigor010: Primary analysis from a phase III randomized study of adjuvant atezolizumab versus observation in high-risk muscle-invasive urothelial carcinoma. ASCO20 Virtual Scientific Program. Abstract 5000.

12. Novartis: Novartis announces positive result of phase III study with radioligand therapy 177Lu-PSMA-617 in patients with advanced prostate cancer. Available at https://www.novartis.com/news/media-releases/novartis-announces-positive-result-phase-iii-study-radioligand-therapy-177lu-psma-617-patients-advanced-prostate-cancer. Accessed April 16, 2021.

13. Hofman MS, Emmett L, Sandhu SK, et al: 177Lu-PSMA-617 versus cabazitaxel in metastatic castration-resistant prostate cancer progressing after docetaxel: Updated results including progression-free survival and patient-reported outcomes (TheraP ANZUP). 2021 Genitourinary Cancers Symposium. Abstract 6. Presented February 11, 2021.

14. de Bono J, Mateo J, Fizazi K, et al: Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med 382:2091-2102, 2020.