ASCO 2021 Recap: What urologists need to know

The 2021 ASCO Annual meeting has come and gone, with its annual release of thousands of abstracts across every tumor type. Here are the key genitourinary cancer highlights for the practicing urologist.

Prostate Cancer: Dawn of the PSMA era

The major buzz in prostate cancer at ASCO was the reporting of the phase 3 VISION trial results of the targeted radioligand therapy 177Lu-PSMA-617 (LuPSMA) in patients with progressive PSMA-positive metastatic castration-resistant prostate cancer (mCRPC).¹ The results of the trial showed that adding LuPSMA to standard of care (SOC) led to a nearly 40% reduction in the risk of death versus SOC alone.

The open-label phase 3 VISION trial (NCT03511664) included 831 patients with progressive PSMA-positive mCRPC who received at least 1 novel androgen axis drug (eg, enzalutamide [Xtandi] or abiraterone acetate [Zytiga]) and were previously treated with 1 to 2 taxane regimens. Patients were randomized in a 2:1 ratio to LuPSMA (n = 551) plus SOC or SOC alone (n = 280).

The median overall survival (OS) was 15.3 months in the LuPSMA arm versus 11.3 months in the SOC alone arm, translating to a 38% reduction in the risk of death (HR, 0.62; P <.001). The median radiographic progression-free survival was 8.7 versus 3.4 months, respectively (HR, 0.40; P <.001). The objective response rates and disease control rates were 29.8% versus 1.7% and 89.0% versus 66.7%, respectively.

Based on the VISION data, the FDA recently granted LuPSMA a Breakthrough Therapy Designation in this setting. The designation will expedite the development and regulatory review of LuPSMA. The FDA has already approved 2 PSMA PET imaging agents for prostate cancer: piflufolastat F 18 (Pylarify) and Ga 68 PSMA-11. LuPSMA is now on track to likely become the first PSMA-targeted agent approved in the space.

Research presented at ASCO also showed how other novel PSMA-targeted agents are rapidly emerging on the heels of LuPSMA. One such study highlighted how the investigational PSMA-targeted compound 225Ac-J591 demonstrated promising clinical activity with a tolerable safety profile in patients with progressive mCRPC who had previously received 1 or more androgen receptor–pathway inhibitors (eg, abiraterone, enzalutamide).² In a cohort of 32 men, 68.8% of patients had at least some level of PSA decline and 43.8% had a PSA decline of over 50%.

Other abstracts hinted at some of the broader impact the PSMA revolution might have in prostate cancer. Findings from a phase 1b study showed that a single dose of LuPSMA primed prostate tumors to respond to the immune checkpoint inhibitor pembrolizumab (Keytruda).³ Among 18 patients with mCRPC who received the single LuPSMA dose and an extensive regimen of pembrolizumab, 44% (n = 8) achieved a response. Five of these patients—all of whom were microsatellite stable, homologous recombination deficiency wild-type—reached a response greater than 8 months.

Bladder-sparing studies break through

Several abstracts presented at ASCO highlighted how integrating immune checkpoint inhibitors into bladder-sparing approaches may enhance the efficacy of these strategies in patients with bladder cancer.

“The biggest impact from studies at ASCO this year in the bladder cancer field had to do with bladder-sparing approaches, and the studies really mark a ‘new dawn’ in bladder-sparing approaches in bladder cancer in terms of integrating immune checkpoint blockade with radiation or even without radiation to achieve bladder sparing,” Matthew Galsky, MD, said in an interview with Urology Times during the meeting.

2 ASCO abstracts in particular demonstrated the emergence of immune checkpoint inhibitors as a major component of the bladder-sparing treatment paradigm.

Findings from the phase 2 HCRN GU16-257 trial showed that combining transurethral resection of the bladder tumor (TURBT) with nivolumab (Opdivo) and chemotherapy is a promising bladder-sparing approach in patients with muscle-invasive bladder cancer (MIBC).⁴

The study enrolled 76 patients with cisplatin-eligible cT2 to T4aN0M0 clinically localized urothelial bladder cancer. At the time of the data cutoff, 64 patients had completed clinical restaging. Of these patients, 31 (48%) achieved a clinical CR. Thirty of these patients chose not to undergo cystectomy and instead receive an additional 4 months of nivolumab monotherapy. Only 1 patient opted for immediate cystectomy. On surgical pathology, that patient had a low-grade papillary tumor. The remaining 33 patients did not reach a clinical CR and cystectomy was recommended.

The other key abstract was an early analysis from a phase 2 study showing positive efficacy and safety signals with pembrolizumab in combination with gemcitabine and concurrent hypofractionated radiotherapy (RT) in patients with MIBC.⁵

Patients received a single dose of pembrolizumab at 200 mg followed in 2 to 3 weeks by maximal transurethral resection of the bladder tumor and then whole-bladder RT with twice weekly gemcitabine at 27 mg/m2 and pembrolizumab every 3 weeks for 3 doses. Six patients were enrolled in a safety cohort, and 48 patients were enrolled in an efficacy cohort.

A total of 42 patients (85%) completed all protocol therapy in the study. Twelve-week complete response was 100% in the safety cohort and 77% in the efficacy cohort. The investigators reported a 1-year bladder-intact disease-free survival rate in the efficacy cohort of 88%. The rate increased slightly to 89% when the safety cohort was added. Metastases-free survival was 85% at 1-year follow-up for the entire cohort.

Adjuvant immunotherapy ascends in RCC

The main news from ASCO in the kidney cancer arena was the report of the results from the phase 3 KEYNOTE-564 trial showing that adjuvant pembrolizumab led to a significant reduction in the risk of disease recurrence or death versus placebo in patients with clear cell renal cell carcinoma (RCC).⁶ The results showed that adjuvant pembrolizumab induced a 32% reduction in the risk of disease recurrence or death compared with placebo (HR, 0.68; P = .0010).

The standard-of-care treatment for patients with locoregional RCC is surgery; however, nearly half of patients eventually experience disease recurrence. Currently, there is no standard adjuvant systemic therapy that is supported by high levels of evidence worldwide.

“KEYNOTE-564 is the first positive phase 3 study of an adjuvant immunotherapy for patients with RCC. Pembrolizumab is a potential new standard of care for patients with RCC in the adjuvant setting,” lead study author Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology, director of the Kidney Cancer Center, and senior physician at Dana-Farber Cancer Institute, as well as Jerome and Nancy Kohlberg chair and professor of medicine at Harvard Medical School, said when reporting the results.

References

1. Morris MJ, De Bono JS, Chi KN, et al. Phase 3 study of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer (VISION). J Clin Oncol 39, 2021 (suppl 15; abstr LBA4). 10.1200/JCO.2021.39.15_suppl.LBA4

2. Tagawa ST, Sun M, Sartor AO, et al. Phase I study of 225Ac-J591 for men with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol 39, 2021 (suppl 15; abstr 5015). doi: 10.1200/JCO.2021.39.15_suppl.5015.

3. Aggarwal RR, Sam SL, Koshkin VS, et al. Immunogenic priming with 177Lu-PSMA-617 plus pembrolizumab in metastatic castration resistant prostate cancer (mCRPC): A phase 1b study. ­­ J Clin Oncol 39, 2021 (suppl 15; abstr 5053). doi: 10.1200/JCO.2021.39.15_suppl.5053

4. Galsky MD, Daneshmand S, Chan KG et al. Phase 2 trial of gemcitabine, cisplatin, plus nivolumab with selective bladder sparing in patients with muscle- invasive bladder cancer (MIBC): HCRN GU 16-257. J Clin Oncol 39, 2021 (suppl 15; abstr 4503). doi: 10.1200/JCO.2021.39.15_suppl.4503

5. Balar AV, Milowsky MI, O’Donnell PH, et al. Pembrolizumab (pembro) in combination with gemcitabine (Gem) and concurrent hypofractionated radiation therapy (RT) as bladder sparing treatment for muscle-invasive urothelial cancer of the bladder (MIBC): A multicenter phase 2 trial. J Clin Oncol 39, 2021 (suppl 15; abstr 4504). doi: 10.1200/JCO.2021.39.15_suppl.4504

6. 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 39, 2021 (suppl 15; abstr LBA5). doi: 10.1200/JCO.2021.39.15_suppl.LBA5