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Genitourinary Oncology Highlights From the ASCO Annual Conference 2023

Op-Med is a collection of original articles contributed by Doximity members.

Presentations at the ASCO annual conference in 2023 consolidated the recent advances in the therapy and understanding of major GU cancers. Multiple novel hormonal agents (NHA) (enzalutamide, abiraterone, darolutamide, apalutamide), chemotherapeutic (cabazitaxel, docetaxel, mitoxantrone), radiopharmaceuticals (radium223, Lu-PSMA), PARP inhibitors (olaparib, rucaparib) and immunotherapeutic agents (pembrolizumab for microsatellite instability or tumor mutation burden high tumors, sipuleucel-T) are components of the therapeutic armamentarium for prostate cancer. The development of rational combinations of agents has become an important direction for drug development. Indeed, the administration of several lines of monotherapy is not efficient, given the attrition of patients eligible for systemic therapy with progression. The combination of NHAs alone or with docetaxel and androgen deprivation therapy (ADT) have extended overall survival (OS) and are already established for metastatic castration-sensitive prostate cancer (mCSPC). Recently, the combination of PARP inhibitors and NHAs (olaparib + abiraterone acetate, talazoparib + enzalutamide) as first-line therapy for metastatic castration-resistant prostate cancer (mCRPC) have yielded benefits in radiographic progression-free survival (rPFS). At ASCO 2023, an updated analysis of the TALAPRO-2 Phase III trial reported a significant and clinically meaningful improvement in rPFS for talazoparib + enzalutamide over enzalutamide alone as first-line treatment in mCRPC patients with homologous recombination repair (HRR) gene alterations. Moreover, a delay of deterioration in quality of life (QoL) was observed. Earlier in 2023, TALAPRO-2 had been already reported to improve rPFS in unselected mCRPC patients. The benefit was more robust in those with BRCA1/2 alterations. Thus, these data appear similar to data from the PROPEL Phase III trial, which demonstrated improved rPFS regardless of HRR alterations. However, in a recent decision, the US FDA approved the combination of abiraterone acetate and olaparib only for the BRCA mutant mCRPC population based on an exploratory subgroup analysis in which BRCA mutations appeared to be the prime driver of improved outcomes with this combination. In the 85 patients with BRCA mutations (11% of population), rPFS exhibited a robust improvement (HR 0.24 [95% CI: 0.12, 0.45]) and was accompanied by improved OS too (HR 0.30 [95% CI: 0.15, 0.59]). In the 711 patients (89% of ITT population) without BRCA mutations, the rPFS HR was 0.77 (95% CI: 0.63, 0.96) and the OS HR was 0.92 (95% CI: 0.74, 1.14). Intriguingly, the combination of olaparib and abiraterone acetate was approved in all mCRPC patients regardless of HRR or BRCA mutations in Europe. This discord between regulatory approvals in the US and Europe is intriguing and it remains to be seen how the regulatory agencies will interpret data from the similar TALAPRO-2 trial. Finally, a Phase I trial demonstrated that a novel combination of Lu-PSMA-617 and olaparib was safe and exhibited promising activity in mCRPC and further development appeared warranted.

At ASCO 2023, the PEACE-1 Phase III trial reported a benefit in rPFS and freedom from castration-resistance for prostate radiation in men with de novo, low-volume mCSPC receiving intensified systemic therapy with ADT and abiraterone acetate with or without docetaxel. Moreover, prostate irradiation reduced serious genitourinary events (e.g., need for ureter stenting, nephrostomy, TURP, catheterization). Hence these data are similar but not identical to the prior data from STAMPEDE that demonstrated a benefit for prostate radiation in those with low volume metastatic disease receiving less intensive systemic therapy with ADT alone. An ongoing US Intergroup phase III trial S1802 is evaluating the role of radical prostatectomy or radiation of the prostate in such patients. 

Switching gears to renal cell carcinoma (RCC), the combination of PD1 and CTLA4 (nivolumab plus ipilimumab for poor or intermediate risk disease) and multiple VEGF + PD1/L1 inhibitor combinations (approved across all risk groups) have transformed first-line therapy. A couple of presentations updated data from the previously reported KEYNOTE426 (Axitinib+Pembrolizumab) and CLEAR (Lenvatinib+Pembrolizumab) Phase III trials, which confirmed continued benefit for these combinations vs. sunitinib. At ASCO-2023, the CONTACT-03 phase III trial was presented, which investigated the impact of PD-(L)1 inhibitor combined with cabozantinib 60 mg once daily following immediate prior PD1/L1 inhibitor therapy. Unfortunately, the addition of atezolizumab to cabozantinib increased toxicities and did not improve clinical outcomes. 

The therapeutic landscape of metastatic urothelial carcinoma (mUC) has been radically altered by the approval of switch maintenance avelumab following stable or responding disease with 4-6 cycles of platinum-based chemotherapy. Combination Enfortumab Vedotin (EV), a Nectin4 targeting antibody drug conjugate (ADC)+pembrolizumab received accelerated approval by the US FDA for cisplatin-ineligible advanced UC in April 2023 based on the combined results from cohorts A (Phase Ib) and K (Phase II) of EV103. In an updated analysis of cohort A of EV103 (n=45) presented at ASCO 2023, EV+pembrolizumab continued to demonstrate promising ORR (73.1%), durable responses (median 22.1 mo) and survival (median 26.1 mo) as first-line therapy (n=45) after 4-year follow-up without new safety concerns. Results of phase III EV302 trial comparing EV+pembrolizumab vs. platinum-based chemo in cisplatin-eligible and ineligible patients are awaited. Although the combination of gemcitabine-platinum with PD1/L1 inhibitors has not improved outcomes definitively to change the standard of care, the cisplatin-based backbone appears to hold promise and has exhibited a signal of more robust synergism with atezolizumab (IMvigor130) as presented at ASCO 2023. 

EV is also approved as salvage therapy, while sacituzumab govitecan (Trop2 targeting ADC) and erdafitinib (pan-FGFR inhibitor for those with somatic FGFR2 or FGFR3 activating fusions/mutations) have received accelerated approvals for the salvage therapy setting based on Phase II trials. At ASCO 2023, the Phase III THOR trial reported that erdafitinib extended OS vs. taxane or vinflinine chemotherapy (median 12.1 vs. 7.8 months, HR 0.64, p=0.005) in advanced UC (n=266) with FGFR3/2 activating mutations/fusions who progressed after 1-2 prior treatments including a PD1/L1 inhibitor. PFS (5.6 vs. 2.7 months, HR 0.58) and ORR (46 v 12%) also improved. Toxicities were as expected. These results in the post PD1/L1 inhibitor setting are practice-changing. The outcomes in the previous Phase II trial had led to US FDA accelerated approval in the post-platinum setting in 2019. Combination Erdafitinib+Cetrelimab (PD1 inhibitor) exhibited promising activity (ORR 54.5%, CR 13.6%) as first-line therapy for cisplatin-ineligible advanced UC (n=44) in the NORSE phase II trial. The activity of erdafitinib monotherapy (n=43) was consistent with prior data in salvage settings (ORR 44.2%, CR 2.3%). The safety profile was consistent with prior data. The results suggest that the combination may provide incremental benefit and further investigation may be warranted. However, the trial was not designed for formal comparison of the arms. 

The SWOG S1011 Phase III trial reported that patients (n=618) with muscle-invasive bladder cancer (MIBC) undergoing radical cystectomy and extended lymph node dissection (ELND) had increased node yield and higher pN stage, but no DFS or OS benefit v pelvic standard lymph node dissection (SLND). ELND was also associated with more grade 3-4 complications (16 v 8%) and post-op mortality in 90 days (16 v 9 deaths). Data are practice-impacting and support standard pelvic lymph node dissection. The VESPER Phase III trial was updated to demonstrate that perioperative (neoadjuvant 88%, adjuvant 12%) dose-dense (dd) MVAC x 6 cycles v GC x 4 cycles showed a trend for improved OS in the overall group (n=500, HR=0.77, p=0.078), and improved OS in the neoadjuvant group (n=437, HR=0.71, p=0.032). The primary endpoint of PFS in the overall group was previously reported and not met. While secondary endpoints of PFS & OS in the neoadjuvant group improved with ddMVAC, the trial administered 6 cycles of ddMVAC (to achieve similar duration of therapy in both arms), which confounds the results. Both ddMVAC and GC (3-4 cycles) are considered reasonable as peri-operative chemotherapy for cT2-T4aN0 MIBC. Finally, the potential of bladder-preserving therapy for MIBC was demonstrated by combination pembrolizumab + twice weekly gemcitabine + hypofractionated radiation in an update of a Phase II trial, which demonstrated a promising Bladder-Intact disease-free survival (BIDFS) in 54 patients. 

Thus, the annual ASCO conference 2023 provided encouraging and multiple advances across urologic cancers. While we make advances with new agents, it is important to also learn from trials that failed to demonstrate benefits and to employ the principles of precision medicine. A better understanding of tumor biology is critically important to make large advances. Finally, given the explosion of new agents, greater investment into a decentralized clinical trial paradigm is necessary. Education of both patients and oncologists is important to highlight clinical trials as a standard of care and even a preferred standard of care in most instances.

Dr. Sonpavde is on the advisory board of EMD Serono, BMS, Merck, Seattle Genetics/Astellas, Janssen, Bicycle Therapeutics, Pfizer, Gilead, Scholar Rock, G1 Therapeutics, Eli Lilly/Loxo Oncology, Lucence Health, IMV, and Vial. He is a consultant/Scientific Advisory Board for Suba Therapeutics and Syapse. He has research support to institution from Sanofi, Astrazeneca, Gilead, Helsinn, Lucence, EMD Serono, Jazz Therapeutics, and Genecentric. He is a speaker for BIO – INFORMAÇÃO BRASILEIRA DE ONCOLOGIA Ltda, Seagen, Gilead, Natera, and Exelixis. He is on the Data safety monitoring committee for Mereo. His spouse is employed by Myriad, and he receives Writing/Editor fees from Uptodate and Elsevier Practice Update Bladder Cancer Center of Excellence.

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