Here, I attempt to capture the major genitourinary (GU) studies presented at the ASCO annual conference in 2021. In the arena of advanced prostate cancer, oncologists have already incorporated multiple new androgen inhibitors (enzalutamide, abiraterone, darolutamide, apalutamide), chemotherapy (cabazitaxel, docetaxel), radiopharmaceuticals (radium223), PARP inhibitors (olaparib, rucaparib), and immune checkpoint inhibitors (pembrolizumab for microsatellite instability or tumor mutation burden high tumors) in the management of this disease. At ASCO 2021, a couple of practice-changing or potentially practice-impacting prostate cancer trials were reported. The VISION trial reported the improvement of survival with targeted radioligand therapy using 177Lu-PSMA-617 (LuPSMA) in metastatic castration-resistant prostate cancer following prior androgen inhibitors and taxane chemotherapy. LuPSMA yielded a 4-month improvement in median overall survival versus standard of care (HR 0.62) and a 5.3-month improvement (HR, 0.40) in median radiographic progression-free survival (rPFS). The PEACE-1 trial reported that abiraterone combined with androgen deprivation therapy (ADT) with or without docetaxel for metastatic castration-sensitive prostate cancer improved rPFS, while adding radiotherapy to the prostate did not. While survival data are not mature, the impressive extension of rPFS (median 2 vs. 4.5 years) appear highly promising to support the combination of docetaxel and abiraterone with ADT. Further follow-up of PEACE-1 and ENZAMET (where adding enzalutamide to ADT and docetaxel also prolonged PFS but not survival) is also required to discern whether the results with these aggressive combinations warrant a change of clinical practice.
Switching gears to renal cell carcinoma (RCC), the combination of PD1 and CTLA4 (nivolumab plus ipilimumab) and multiple VEGF and PD1/L1 inhibitors have transformed first-line therapy. A phase III trial evaluating combination of cabozantinib with both ipilimumab and nivolumab is eagerly awaited. It was a natural application of the data to evaluate adjuvant therapy using immune checkpoint inhibitors. Indeed, the phase III KEYNOTE-564 study reported that adjuvant therapy with pembrolizumab following surgery for high risk clear cell RCC led to a 32% reduction in the risk of disease recurrence or death compared with placebo. Survival data require longer follow-up to be interpretable. These data provide evidence supporting a practice-changing impact for adjuvant pembrolizumab. Although sunitinib is approved by the U.S. FDA as adjuvant therapy in the U.S. based on PFS prolongation, the therapeutic index is considered suboptimal in general.
The therapeutic landscape of metastatic urothelial carcinoma has been radically altered by the approval of switch maintenance avelumab following stable or responding disease with 4-6 cycles of platinum-based chemotherapy. Moreover, a couple of antibody drug conjugates (enfortumab vedotin, sacituzumab govitecan) and a targeted small molecule FGFR inhibitor (erdafitinib) are now approved for the salvage therapy setting. Moreover, while the combination of gemcitabine-platinum with PD1/L1 inhibitors has not yet changed the standard of care, the cisplatin-based backbone appears to hold promise and has exhibited a signal of more robust synergism with both atezolizumab (IMvigor130) and pembrolizumab (KEYNOTE361). Further advances await the ongoing key first line phase III trials evaluating the combination of enfortumab vedotin with pembrolizumab and of ipilimumab with nivolumab. The potential arrival of adjuvant nivolumab to the clinic based on the results of CHECKMATE274 (improved disease-free survival in all patients and PD-L1 high expressing patients) may spawn a new spectrum of trials for metastatic disease. Preliminarily, tumor-informed circulating tumor (ct)-DNA appears promising to identify high-risk patients with minimal residual disease who may benefit from adjuvant atezolizumab. While there were no practice-changing data for urothelial carcinoma presented at ASCO-2021, improved quality of life was demonstrated for enfortumab vedotin compared to chemotherapy from the EV301 phase III trial conducted in post-platinum and PD1/L1 inhibitor treated patients. The promising potential for multiple strategies as bladder-preserving therapy was demonstrated by cisplatin-based chemotherapy + PD1 inhibitor therapy, CTLA4 + PD-L1 inhibitor therapy combined with concurrent radiation, and PD1 inhibitor + twice weekly gemcitabine + hypofractionated radiation. The combination of multiple VEGF and PD1/L1 inhibitors appear promising and one of them (Lenvatinib plus pembrolizumab) is undergoing phase III evaluation. Feladilimab, an ICOS agonist, demonstrated a signal of activity and may warrant further study as monotherapy or in combination with pembrolizumab.
Thus, the annual ASCO conference 2021 maintained the exciting, inspiring, and dramatic pace of advances we have already witnessed in the arena of GU cancers. While we make advances with new agents, it is important to not lose sight of, and also learn from, trials that failed to demonstrate benefits, (e.g., DNA damage repair inhibitors such as PARP inhibitors and ATR inhibitors have been disappointing in unselected mUC patients, and even in genomically selected patients in the case of rucaparib). The go/no go decision to proceed to phase III trials is still being made sub-optimally by comparison of outcomes across datasets without formally employing known clinical prognostic models. While research continues to make incremental advances in outcomes, it is also important to have a separate focus on high-risk, high-reward research based on solid biologic rationale and at least preliminary preclinical data. Finally, the regulatory burden of conducting trials is challenging and needs to be addressed with reasonable reforms in order to achieve the primary goal of improving the care of cancer patients.
Dr. Guru Sonpavde has received grants from Sanofi, Astrazeneca, Immunomedics/Gilead, QED, Predicine, and BMS. He has also received consulting fees from BMS, Genentech, EMD Serono, Merck, Sanofi, Seattle Genetics/Astellas, Astrazeneca, Exelixis, Janssen, Bicycle Therapeutics, Pfizer, Immunomedics/Gilead, Scholar Rock, and G1 Therapeutics.