The past year has witnessed tremendous advances in genitourinary oncology. I am pleased to review these findings in this year’s Genitourinary Oncology Almanac from The ASCO Post. I hope that you will find this roadmap helpful in highlighting a selection of these exciting developments.
Bishoy M. Faltas, MD
Checkpoint Inhibition and Antibody-Drug Conjugates in Urothelial Carcinoma
In our area of focus, urothelial carcinoma, immune checkpoint inhibitors are already making inroads into the perioperative setting after transforming the treatment of metastatic urothelial cancer. The phase III CheckMate 274 trial met its primary endpoint demonstrating that adjuvant nivolumab improved disease-free survival compared to placebo in unselected patients, with a more pronounced benefit observed in patients with tumor PD-L1 expression ≥ 1%.1 Based on these data, the U.S. Food and Drug Administration (FDA) approved nivolumab for the adjuvant treatment of patients with urothelial carcinoma who are at high risk of recurrence after undergoing radical surgical resection. However, the overall survival data are still pending. Results from the AMBASSADOR trial (Clinical Trials.gov identifier NCT03244384) will add to the growing body of evidence supporting the role of adjuvant immunotherapy in selected patients with high-risk urothelial cancer after definitive surgical resection.
We continue to see emerging positive data from clinical trials of antibody-drug conjugates in different clinical settings. In patients with previously treated metastatic urothelial carcinoma, the phase III EV-301 trial showed that enfortumab vedotin-ejfv improves overall survival compared to chemotherapy.2 The phase II TROPHY-U-01 trial demonstrated the efficacy of another antibody-drug conjugate, sacituzumab govitecan-hziy, leading to approval of this agent by the FDA.3
The combination of immune checkpoint inhibitors and antibody-drug conjugates seems to be particularly promising. For example, at the 2022 ASCO Genitourinary Cancer Symposium, data from cohort 3 of TROPHY-U-01 demonstrated that treatment with sacituzumab govitecan and pembrolizumab led to encouraging responses in the second-line setting.4 Combined with previous data showing promising efficacy signals from the combination of enfortumab vedotin and pembrolizumab, these results highlight the promise of combining antibody-drug conjugates with immunotherapy in patients with urothelial carcinoma across different clinical stages.
While cisplatin-based chemotherapy continues to be the backbone of neoadjuvant therapy for clinically localized muscle-invasive bladder cancer,5 we are starting to see immune checkpoint inhibitors and antibody-drug conjugates show antitumor activity in the neoadjuvant setting. The EV-103 cohort H highlighted the promise of enfortumab vedotin for patients with muscle-invasive bladder cancer who are cisplatin-ineligible.6 The trial showed a pathologic complete response rate comparable to that historically obtained with chemotherapy.
New Options for Patients With Castration-Resistant Prostate Cancer
This year, the therapeutic options for patients with advanced prostate cancer continued to expand and now include a new class of radioligand therapies that deliver beta-particle radiation to prostate-specific membrane antigen (PSMA)-expressing cells. Lutetium-177–PSMA-617 (LuPSMA) showed prolonged overall survival in patients with metastatic castration-resistant prostate cancer whose disease had progressed after chemotherapy and androgen receptor pathway inhibitors.7 Recently published data show that nomograms integrating clinical factors and PSMA positron-emission tomography scans predict outcomes after LuPSMA in patients with metastatic castration-resistant prostate cancer.8
We continue to see the rise of poly (ADP-ribose) polymerase (PARP) inhibitors, which have now been shown to benefit patients with castration-resistant prostate cancer in the first-line setting in combination with abiraterone acetate, as seen in the phase III MAGNITUDE and PROpel trials.9,10 The details of the germline and somatic homologous recombination mutations, genomic scar mutational signatures, the optimal assays, and the test substrates (tissue vs circulating tumor DNA) are critical for defining the best clinical biomarkers that predict synthetic lethality with PARP inhibition.
Advances and Approvals in Renal Cell Carcinoma
In patients with advanced renal carcinoma, we continue to see additional treatment options, including combinations between targeted therapy and immunotherapy. The CheckMate 9ER phase III study of nivolumab plus cabozantinib demonstrated a significant improvement in progression-free survival, overall survival, and the likelihood of response in patients with previously untreated advanced renal cell carcinoma compared to sunitinib.11 The combination of nivolumab plus cabozantinib is now approved by the FDA as initial therapy for patients with advanced renal cell carcinoma, regardless of risk stratification. Comparisons of this combination with first-line immunotherapy are needed.
Finally, in the adjuvant setting, the updated results from KEYNOTE-564 confirmed the survival benefit of adjuvant pembrolizumab over placebo following nephrectomy for patients with renal cell carcinoma at high risk for recurrence. The data from this trial had led to FDA approval of adjuvant pembrolizumab for this indication.12
Progress in the treatment of genitourinary cancers has been nothing short of extraordinary in 2021. However, it is important to note that the fruits of translational advances are built on foundations of basic science that require serious investments and take years in the making. Response or resistance to these treatments provide critical information to help us understand the biology of these cancers. This in-depth understanding is key to improving our treatment strategies to extend the benefits to as many patients as possible.
DISCLOSURE: Dr. Faltas has served in a consulting or advisory role for Guardant, Janssen, Gilead, BostonGene, QED Therapeutics, and Merck; has received patent royalties from Immunomedics/Gilead; and has received research funding from Eli Lilly and Company.
1. 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.
2. Powles T, Rosenberg JE, Sonpavde GP, et al: Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med 384:1125-1135, 2021.
3. Tagawa ST, Balar AV, Petrylak DP, et al: TROPHY-U-01: A phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors. J Clin Oncol 39:2474-2485, 2021.
4. Grivas P, Pouessel D, Park CH, et al: TROPHY-U-01 Cohort 3: Sacituzumab govitecan in combination with pembrolizumab in patients with metastatic urothelial cancer who progressed after platinum-based regimens. 2022 ASCO Genitourinary Cancers Symposium. Abstract 434. Presented February 18, 2022.
5. Pfister C, Gravis G, Flechon A, et al: Dose-dense methotrexate, vinblastine, doxorubicin and cisplatin (dd-MVAC) or gemcitabine and cisplatin (GC) as perioperative chemotherapy for patients with muscle-invasive bladder cancer. ESMO Congress 2021. Abstract 652O. Presented September 17, 2021.
6. Petrylak D, Flaig TW, Mar N, et al: Study EV-103 Cohort H: Antitumor activity of neoadjuvant treatment with enfortumab vedotin monotherapy in patients with muscle invasive bladder cancer who are cisplatin-ineligible. 2022 ASCO Genitourinary Cancers Symposium. Abstract 435. Presented February 18, 2022.
7. Morris MJ, De Bono JS, Chi KN, et al: Phase III study of lutetium-177–PSMA-617 in patients with metastatic castration-resistant prostate cancer (VISION). 2021 ASCO Annual Meeting. Abstract LBA4. Presented June 6, 2021.
8. Gafita A, Calais J, Grogan TR, et al: Nomograms to predict outcomes after 177Lu-PSMA therapy in men with metastatic castration-resistant prostate cancer: an international, multicentre, retrospective study. Lancet Oncol 22:1115-1125, 2021.
9. Chi KN, Rathkopf DE, Smith MR, et al: Phase III MAGNITUDE study: First results of niraparib with abiraterone acetate and prednisone as first-line therapy in patients with metastatic castration-resistant prostate cancer with and without homologous recombination repair gene alterations. 2022 ASCO Genitourinary Cancers Symposium. Abstract 12. Presented February 17, 2022.
10. Saad F, Armstrong A, Thiery-Vuillemin T, et al: PROpel: Phase III trial of olaparib and abiraterone versus placebo and abiraterone as first-line therapy for patients with metastatic castration-resistant prostate cancer. 2022 ASCO Genitourinary Cancers Symposium. Abstract 11. Presented February 17, 2022.
11. Choueiri TK, Powles T, Burotto M, et al: Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 384:829-841, 2021.
12. Choueiri TK, Tomczak P, Park SH, et al: Pembrolizumab as post nephrectomy adjuvant therapy for patients with renal cell carcinoma: Results from 30-month follow-up of KEYNOTE-564. 2022 ASCO Genitourinary Cancers Symposium. Abstract 290. Presented February 19, 2022.