2021 was another busy year in the urology space, with multiple drugs and devices receiving FDA approval. In this article, we look back on the notable developments in treatment and diagnostics within the specialty.
The prostate cancer drug relugolix (Orgovyx) is now available in the United States through authorized specialty distributors. The gonadotropin-releasing hormone receptor antagonist was approved in December 2020 for the treatment of patients with advanced prostate cancer. The approval was based on data from the phase 3 HERO study (NCT03085095), which showed that 96.7% of patients randomized to relugolix maintained castration through 48 weeks, compared with 88.8% of patients receiving leuprolide (P < .001).1 The benefit with relugolix was sustained across all major secondary end points (P < .001). Relugolix was also associated with a 54% lower risk of major adverse cardiovascular events compared with leuprolide (HR, 0.46).
The FDA updated the label for darolutamide (Nubeqa) in nonmetastatic castration-resistant prostate cancer (CRPC) to include overall survival (OS) data from the pivotal phase 3 ARAMIS trial. In the ARAMIS trial (NCT02200614), adding darolutamide to androgen-deprivation therapy (ADT) reduced the risk of death by 31% compared with ADT plus placebo in men with nonmetastatic CRPC (HR, 0.69; P = .003).2 At a median follow-up of 29 months, the 3-year OS rates were 83% and 77% in the darolutamide and placebo arms, respectively. This OS benefit was reached even though over half (55%) of the patients in the control arm received darolutamide or other subsequent treatments after the study was unblinded.
The combination of nivolumab (Opdivo) and cabozantinib (Cabometyx) was approved by the FDA as a frontline treatment for patients with advanced renal cell carcinoma (RCC). The approval was based on findings from the phase 3 CheckMate 9ER trial (NCT03141177), which showed that the combination reduced the risk of disease progression or death by 49% vs sunitinib (Sutent) in treatment-naïve patients with advanced RCC, with a median progression-free survival (PFS) of 16.6 months vs 8.3 months, respectively (HR, 0.51; P < .0001).3 Additional findings showed that at a median follow-up of 18.1 months, the median OS was not reached in either arm, and there was a 40% reduction in the risk of death with the combination (HR, 0.60; P = .001).
The FDA approved expanded MRI labeling for the InterStim II and InterStim Micro sacral neuromodulation systems that use SureScan MRI leads. The devices are used to treat patients with bladder and bowel control conditions. Medtronic, the developer of the devices, reported in a news release that the updated MRI guidelines in the label expand the range of MRI scan parameters and allow a briefer waiting period between MRI scans.4
AstraZeneca voluntarily withdrew the FDA indication for the PD-L1 inhibitor durvalumab (Imfinzi) for use in previously treated patients with locally advanced or metastatic bladder cancer. Durvalumab received an accelerated approval from the FDA for this indication in May 2017 based on the single-arm phase 1/2 Study 1108. However, an FDA accelerated approval is contingent upon the results of a confirmatory trial and in March 2020, AstraZeneca reported that the phase 3 DANUBE trial (NCT02516241) exploring durvalumab in frontline urothelial cancer missed its primary end points.5
The FDA approved the third-generation version of Axonics Modulation Technologies’ rechargeable implantable neurostimulator (INS) for the treatment of patients with urinary and bladder dysfunction.6 The INS device was launched commercially in the United States in November 2019. A second-generation version approved in April 2020 prolonged the device’s recharge interval. The third-generation model upgrades the software embedded in the device and enhances the functionality of the remote control, used by patients to monitor their stimulation level and the need to recharge the stimulator.
Roche (Genentech) voluntarily withdrew the FDA indication for the PD-L1 inhibitor atezolizumab (Tecentriq) for use in patients with locally advanced or metastatic urothelial carcinoma (mUC) previously treated with platinum-based chemotherapy. Atezolizumab received an accelerated approval from the FDA for this indication in May 2016 based on cohort data from the phase 2 IMvigor210 study (NCT02108652). However, an FDA accelerated approval is contingent upon the results of a confirmatory trial and in May 2017, Roche reported that the phase 3 IMvigor211 study (NCT02302807) exploring atezolizumab in the second-line setting for patients with locally advanced or mUC missed its primary end point of improving OS.7
The FDA approved tivozanib (Fotivda) for the treatment of adult patients with relapsed or refractory advanced RCC who have received 2 or more prior systemic therapies. The approval was based on data from the phase 3 TIVO-3 trial (NCT02627963), in which the VEGF tyrosine kinase inhibitor tivozanib demonstrated a significant improvement in PFS compared with sorafenib (Nexavar), with similar OS in patients with highly relapsed/refractory metastatic RCC.8
The β3-adrenoceptor agonist vibegron (Gemtesa) was made commercially available in the United States for the treatment of adult patients with overactive bladder with symptoms of urge urinary incontinence (UUI), urgency, and urinary frequency. The FDA approved vibegron on December 23, 2020, for use in this setting based on the phase 3 EMPOWUR trial (NCT03492281). In the primary study analysis, at 12 weeks, vibegron showed a mean change from baseline in the average daily number of micturitions of –1.8 compared with –1.3 for placebo and –1.6 for tolterodine (P < .001).9 The mean change from baseline in UUI episodes was –2.0, –1.4, and –1.8, respectively.
The FDA granted an accelerated approval to sacituzumab govitecan (Trodelvy) for the treatment of patients with locally advanced or mUC who previously received a platinum-containing chemotherapy and either a PD-1 or PD-L1 inhibitor. The approval of the antibody-drug conjugate was based on the final data from cohort 1 of the phase 2 TROPHY-U-01 trial (NCT03547973), which showed that sacituzumab govitecan induced an overall response rate of 27% in heavily pretreated patients with mUC following the failure of both platinum-based chemotherapy and checkpoint inhibition.10
The FDA granted clearance to UroViu Corporation to market the Uro-G flexible, portable, single-use cystoscope.11 The self-contained Uro-G device has a fully deflectable tip, which offers urologists the flexibility to use the device for diagnostic or interventional procedures in any room in their clinic. UroViu also maintains that using the Uro-G single-use device typically translates to a lower cost per procedure vs reusable options.
The FDA approved the PSMA-PET imaging agent piflufolastat F 18 (Pylarify) for identifying suspected metastasis or recurrence of prostate cancer. The approval was based on findings from the CONDOR12 (NCT03739684) and OSPREY (NCT02981368) studies. In the CONDOR study, 63.9% of men with biochemically recurrent prostate cancer who had no evidence of disease on standard-of-care imaging had a change in intended management after their piflufolastat F 18 scan.
The FDA approved a ready-to-use 6-month subcutaneous depot formulation of leuprolide mesylate (Camcevi 42 mg) for the treatment of patients with advanced prostate cancer. The approval was based on findings from a phase 3 trial (NCT02234115) in which the primary efficacy end points were the percentage of subjects with suppression of serum testosterone (≤ 50 ng/dL) by day 28 and from day 28 to day 336.13 These primary end points were successfully achieved; 97% of subjects had a serum testosterone level equal to or less than 50 ng/dL by the end of the trial. Further, 95.9% of patients reached a serum testosterone level equal to or less than 20 ng/dL.
The FDA granted a regular approval to enfortumab vedotin-ejfv (Padcev) for the treatment of patients with locally advanced or metastatic urothelial cancer who have previously received a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy; or patients who are ineligible for cisplatin-containing chemotherapy and have previously received 1 or more prior lines of therapy.14 The approval was based on findings from the EV-301 (NCT03474107) and EV-201 (NCT03219333) trials. In the phase 3 EV-301 trial, enfortumab vedotin reduced the risk of death by 30% vs chemotherapy in patients with heavily pretreated locally advanced or metastatic urothelial carcinoma.
The FDA granted 510(k) clearance to Lazarus 3D for its PRE-SURE 3D printing technology for use across all genitourinary conditions.15 The technology produces synthetic, soft-tissue models with a lifelike quality—including bleeding—that allows clinicians to map out and simulate surgeries in preparation for operating on their actual patients. The PRE-SURE system creates the realistic models directly from patient MRI/CT data. Urology areas covered for this FDA clearance include conditions of the prostate, bladder, kidneys, and genitalia.
The FDA approved pembrolizumab (Keytruda) plus lenvatinib (Lenvima) for the first-line treatment of adult patients with advanced RCC. The approval was based on findings from the phase 3 KEYNOTE-581/CLEAR trial (NCT02811861) (Study 307), which showed that frontline therapy with the combination reduced the risk of death by 34% vs sunitinib in patients with advanced RCC.16
The FDA approved belzutifan (Welireg) for adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated RCC, central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors not requiring immediate surgery. The approval was based on data from the phase 2 Study 004 (NCT03401788), which enrolled patients with VHL-associated RCC, as well as nonrenal lesions.17 Belzutifan induced an overall response rate of 49% (n = 30) among 61 patients with VHL-associated RCC.
The FDA granted an accelerated approval to the PD-1 inhibitor dostarlimab-gxly (Jemperli) for the treatment of adult patients with mismatch repair-deficient recurrent or advanced solid tumors, as determined by an FDA-approved test. The approval was supported by results from the ongoing phase 1 GARNET trial (NCT02715284). Across 209 evaluable patients with solid tumors, the PD-1 inhibitor induced an objective response rate of 41.6%.18 The objective response rate was composed of a complete response rate of 9.1% and a partial response rate of 32.5%. The median duration of response was 34.7 months (range, 2.6-35.8+).
The FDA approved nivolumab (Opdivo) for the adjuvant treatment of patients with urothelial carcinoma who are at high risk of recurrence after undergoing radical resection, regardless of prior neoadjuvant chemotherapy, nodal involvement, or PD-L1 status. The approval was based on the randomized, double-blind, phase 3 CheckMate 274 trial (NCT02632409), which evaluated nivolumab in 353 patients vs 356 patients receiving placebo.19 Patients who received nivolumab had a median disease-free survival (DFS) of 20.8 months vs 10.8 months in the placebo arm. Additional findings from the study indicated that 74.5% of patients in the nivolumab arm who had a PD-L1 expression equal to or greater than 1% were alive and disease-free at 6 months vs 55.7% of those in the placebo (HR, 0.55; P < .001).
The FDA converted the accelerated approval of frontline pembrolizumab in advanced bladder cancer to a full approval and revised the indication to cover the treatment of patients with locally advanced or mUC who are not eligible for any platinum-containing chemotherapy.20 Previously, the PD-1 inhibitor was indicated for patients with locally advanced or mUC who were not eligible for cisplatin-containing chemotherapy who had PD-L1–positive tumors, or in patients who were not eligible for any platinum-containing chemotherapy, regardless of PD-L1 status; however, in the confirmatory KEYNOTE-361 trial (NCT02853305), which explored frontline pembrolizumab as a single agent and combined with chemotherapy in patients with advanced or mUC who were eligible for platinum-containing chemotherapy, the dual primary end points of OS and PFS vs standard chemotherapy were not met.
The FDA authorized the marketing of Paige Prostate, an artificial intelligence–based software platform to help pathologists identify prostate cancer when they review slide images from prostate biopsies.21
The standard biopsy review process involves the pathologist examining digitally scanned slide images from prostate biopsies to find areas that are suspicious for cancer. Paige Prostate provides a supplementary assessment of the image and locates the area with the highest probability of harboring cancer. The pathologist can then examine this specific area further if it was not identified on initial assessment.
The FDA approved pembrolizumab for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. The approval was based on data from the phase 3 KEYNOTE-564 trial (NCT03142334), which showed that at a median follow-up of approximately 24 months, the median DFS was not reached with either adjuvant pembrolizumab (n = 496) or placebo (n = 498) as per investigator assessment; however, the HR for DFS showed that pembrolizumab induced a 32% reduction in the risk of disease recurrence or death compared with placebo (HR, 0.68; P = .0010).22
1. Shore ND, Saad F, Cookson MS, et al; HERO Study Investigators. Oral relugolix for androgen-deprivation therapy in advanced prostate cancer. N Engl J Med. 2020;382(23):2187-2196. doi:10.1056/NEJMoa2004325
2. Fizazi K, Shore N, Tammela TL, et al; ARAMIS Investigators. Nonmetastatic, castration-resistant prostate cancer and survival with darolutamide. N Engl J Med. 2020;383(11):1040-1049. doi:10.1056/NEJMoa2001342
3. Choueiri TK, Powles T, Burotto M, et al. Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: first results from the randomized phase 3 CheckMate 9ER trial. Ann Oncol. 2020;31(suppl 4):S1159. doi:10.1016/j.annonc.2020.08.2257
4. Medtronic receives FDA approval for expanded MRI labeling of InterStim SureScan MRI leads. News release. Medtronic. February 18, 2021. Accessed November 20, 2021. https://prn.to/2Zrl6ML
5. Update on phase III DANUBE trial for Imfinzi and tremelimumab in unresectable, stage IV bladder cancer. News release. AstraZeneca. March 6, 2020. Accessed November 21, 2021. https://bit.ly/3cFFeAu
6. Axonics receives FDA approval for third-generation implantable neurostimulator. News release. Axonics. February 16, 2021. Accessed November 21, 2021. https://bit.ly/3uhPIyJ
7. Roche provides update on phase III study of TECENTRIQ (atezolizumab) in people with previously treated advanced bladder cancer. News release. Roche. May 10, 2017. Accessed November 20, 2021. https://bit.ly/3DHK7Gj
8. Pal SK, Escudier B, Atkins MB, et al. TIVO-3: Final OS analysis of a phase III, randomized, controlled, multicenter, open-label study to compare tivozanib to sorafenib in subjects with metastatic renal cell carcinoma (RCC). Presented at: 2020 ASCO Virtual Program; May 27, 2020; virtual. Abstract 5062.
9. Staskin D, Frankel J, Varano S, Shortino D, Jankowich R, Mudd PN Jr. International phase III, randomized, double-blind, placebo and active controlled study to evaluate the safety and efficacy of vibegron in patients with symptoms of overactive bladder: EMPOWUR. J Urol. 2020;204(2):316-324. doi:10.1097/JU.0000000000000807
10. Loriot Y, Balar AV, Petrylak DP, et al. Final results from TROPHY-U-01 cohort 1: a phase 2 open-label study of sacituzumab govitecan (SG) in patients with metastatic urothelial cancer (mUC) and disease progression after platinum (PLT)-based regimens and checkpoint inhibitors. Presented at: ESMO Virtual Congress 2020; September 19-21, 2020; virtual. Abstract LBA24.
11. FDA clearance of the Uro-G completes UroViu Corporation’s suite of portable, single-use, disposable cystoscopes. News release. UroViu Corporation. May 24, 2021. Accessed May 25, 2021. https://bit.ly/2SoZwsi
12. Morris MJ, Rowe SP, Gorin MA, et al; CONDOR Study Group. Diagnostic performance of 18F-DCFPyL-PET/CT in men with biochemically recurrent prostate cancer: results from the CONDOR phase III, multicenter study. Clin Cancer Res. 2021;27(13):3674-3682. doi:10.1158/1078-0432.CCR-20-4573
13. Shore N, Mincik I, DeGuenther M, et al. A phase 3, open-label, multicenter study of a 6-month pre-mixed depot formulation of leuprolide mesylate in advanced prostate cancer patients. World J Urol. 2020;38(1):111-119. doi:10.1007/s00345-019-02741-7
14. FDA grants regular approval to enfortumab vedotin-ejfv for locally advanced or metastatic urothelial cancer. FDA. Updated July 9, 2021. Accessed July 9, 2021. https://bit.ly/3jZoA4D
15. Lazarus 3D announces first FDA clearance for PREoperative SUrgical REhearsal (PRE-SURE) technology. News release. Lazarus 3D. July 29, 2021. Accessed August 27, 2021. https://prn.to/3znDkPT
16. FDA approves Keytruda (pembrolizumab) plus Lenvima (lenvatinib) combination for first-line treatment of adult patients with advanced renal cell carcinoma (RCC). News release. Merck. August 11, 2021. Accessed November 21, 2021. https://bit.ly/3jHFJxW
17. FDA approves belzutifan for cancers associated with von Hippel-Lindau disease. FDA. August 13, 2021. Accessed November 21, 2021. https://bit.ly/3fY5JEw
18. GSK receives FDA accelerated approval for Jemperli (dostarlimab-gxly) for adult patients with mismatch repair-deficient (dMMR) recurrent or advanced solid tumours. News release. GlaxoSmithKline. August 17, 2021. Accessed November 21, 2021. https://bit.ly/3zah8by
19. Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021;384(22):2102-2114. Published correction appears in N Engl J Med. 2021;385(9):864.
20. FDA approves updated indication for Merck’s Keytruda (pembrolizumab) for treatment of certain patients with urothelial carcinoma (bladder cancer). News release. Merck. August 31, 2021. Accessed November 21, 2021. https://bwnews.pr/3kF1dw6
21. FDA authorizes software that can help identify prostate cancer. News release. FDA. September 21, 2021. Accessed November 21, 2021. https://bit.ly/3lKAEGb
22. Choueiri TK, Tomczak P, Park SH, et al. Pembrolizumab vs placebo as post-nephrectomy adjuvant therapy for patients with renal cell carcinoma: randomized, double-blind, phase 3 KEYNOTE-564 study. J Clin Oncol. 2021;39(suppl 18):LBA5. doi:10.1200/JCO.2021.39.15_suppl.LBA5