Francesca Jackson-Spence, PhD

For genitourinary (GU) cancers, 2023 marked a turning point as it was full of unprecedented breakthroughs, particularly in the urothelial cancer space.

From the use of immunotherapy against bladder tumors to the utilization of poly-ADP ribose polymerase (PARP) inhibitors in prostate cancer, the treatment landscape has shifted dramatically. Not only have these advancements demonstrated incremental progress, but some of these updates offer shifts in the ways experts diagnose, treat, and even prevent these diseases.

“[2023] has been 1 of the most exciting years in genitourinary oncology, particularly in the field of bladder cancer. We saw recently at the [European Society of Medical Oncology] 2023 Congress, some outstanding results from the [EV-302] trial [NCT04223856], which certainly will change practice in the treatment [landscape], with an overall survival [OS] for the enfortumab vedotin [Padcev] and pembrolizumab [Keytruda] combination which is unlike anything that's ever been seen before in this field, and we're excited about that,” Francesca Jackson-Spence, PhD, told Targeted Oncology^TM in an interview.

womans bladder cancer: © vitanovski - stock.adobe.com

Bladder Cancer

EV-302

One study that sparked interest in the bladder cancer space was the phase 3 EV-302 trial of the frontline regimen of enfortumab vedotin-ejfv and pembrolizumab.1 Based on data from EV-302, the FDA approved the combination in December 2023 for patients with locally advanced or metastatic urothelial cancer (mUC) who are not eligible to receive cisplatin-containing chemotherapy.

EV-302 compared enfortumab vedotin, an antibody-drug conjugate which targets Nectin-4, in combination with the immune checkpoint inhibitor (ICI), pembrolizumab (EVP arm), to platinum-based chemotherapy.

Prior to this study, Jackson-Spence, clinical research fellow at Barts Cancer Institute, Queen Mary University of London, and Matthew Young, MD, clinical trial fellow, GU Oncology, Barts Cancer Institute, Queen Mary University of London, explained that no other agent, including ICI monotherapy, has beaten the results seen with chemotherapy in this space.

“This combination was the first time that this has been shown to be positive in this setting,” explained Jackson-Spence.

Among previously untreated patients with locally advanced or mUC, a statistically significant improvement in OS was observed with the combination vs chemotherapy, reducing the risk of death by 53% (HR, 0.47; 95% CI, 0.38-0.58; P <.00001). In the EVP arm, the median OS was 31.5 months (95% CI, 25.4-not reached) vs 16.1 months (95% CI, 13.9-18.3) in the chemotherapy arm. The OS benefit was seen regardless of the patient's PD-L1 status or the presence of visceral metastases, and findings were consistent whether the patient was treated with cisplatin or carboplatin.

“This is the first time a treatment has beaten chemotherapy in decades of historical use of chemotherapy in the frontline setting,” Young told Targeted Oncology^TM in an interview.

Matthew Young, MD

In the EVP arm, the median progression-free survival (PFS) was 12.5 months (95% CI, 10.4-16.6) vs 6.3 months (95% CI, 6.2-6.5) with chemotherapy, which resulted in a 55% reduction in the risk of disease progression or death (HR, 0.45; 95% CI, 0.38-0.54; P <.00001).

The toxicity profile of the combination was similar to previous study findings, and no significant safety signals were observed. Overall, the combination was well tolerated.

“An area of interest is going to be further testing these combinations and to see if there's potential for triplet therapy in the future and whether that's tolerable,” explained Jackson-Spence.

“[Enfortumab vedotin] has a bright future, especially in combination with pembrolizumab, and all of the trials that are looking at earlier disease will be keenly awaited for,” said Young.

Other Agents of Interest

Disitamab Vedotin

The HER2-targeted antibody-drug conjugate disitamab vedotin (RC48) is another agent being evaluated and may provide a new treatment option for patients with bladder cancer.²

The agent is being studied in combination with the PD-1 inhibitor toripalimab (Loqtorzi), which demonstrated promising clinical activity with a manageable safety profile in patients with locally advanced or mUC.² Another phase 2 study is evaluating disitamab vedotin alone or in combination with pembrolizumab.

“This is a step towards personalized cancer therapy. We're testing patients for this HER2 mutation present on a number of bladder cancer tumors…If that trial reads positive, that drug may be tested in combination with other agents, such as pembrolizumab or other immune checkpoint inhibitors,” explained Jackson-Spence.

Sacituzumab Govitecan

Experts are eagerly awaiting the results of the TROPHY U-01 (NCT03547973) study, which is evaluating the efficacy and safety of sacituzumab govitecan-hzi (Trodelvy) as monotherapy or in novel combinations for patients with advanced or unresectable mUC who had progressed after prior platinum-based combination chemotherapy and checkpoint inhibitors.³

Among the 38 patients enrolled in cohort 2 of the study, 12 responses to sacituzumab govitecan were observed, all of which were partial and lasted for a median duration of 5.6 months (95% CI, 2.8-13.3). The median PFS after a median follow-up of 9.3 months (range, 0.5-30.6) was 5.6 months (95% CI, 4.1-8.3), and the median OS was 13.5 months (95% CI, 7.6-15.6).

For safety, 68% of patients had grade 3 or higher treatment-related adverse events (TRAEs), including neutropenia (34%), anemia (21%), leukopenia (18%), fatigue (18%), and diarrhea (16%). Commonly reported all-grade TRAEs seen were diarrhea (63%), alopecia (50%), nausea (47%), neutropenia (45%), fatigue (42%), anemia (37%), leukopenia (34%), and decreased appetite (26%).

“The results for sacituzumab with the TROPHY study are to see whether or not there'll be benefit in that population as well, [of] those who received prior treatments,” explained Young.

Kidneys, adrenal glands, genitourinary system, body scan, joint, medical screen 3D render, human anatomy, computer anatomy, body skeleton, X-ray scan: © Leo Viktorov - stock.adobe.com

RCC

Adjuvant therapy in renal cell carcinoma (RCC) has historically been a challenge, with a number of negative trials.

“It's been difficult to prove that patients can live longer with adjuvant treatment, and other immunotherapies have failed. Reasons for that I think are widely discussed in this community, but it's nice to know that we have a treatment that has now proven to let patients live longer after a curative surgery,” said Young.

Adjuvant Setting

KEYNOTE-564

Prior data from the phase 3 KEYNOTE-564 trial (NCT03142334) of pembrolizumab vs placebo led the FDA to approve the agent 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.⁴ At a median follow-up of approximately 24 months, adjuvant pembrolizumab reduced the risk of disease recurrence or death by 32% vs placebo (HR, 0.68; P =.0010).

Updated findings from KEYNOTE-564 showed that as an adjuvant therapy, pembrolizumab demonstrated significant improvements in OS vs placebo in this patient population with no new safety signals observed.

“This was exciting because other immunotherapies have failed to show benefits following nephrectomy. Whether or not that's due to trial design, or differences in drug activity, it is controversial. But an updated press release has claimed a clinically meaningful overall survival signal, which will be the first time we have that in the adjuvant therapy as well,” said Jackson-Spence.

“We're eagerly awaiting the results of the overall survival signal to know what that looks like. I think it's likely to change the strength of recommendation from a guideline perspective,” added Young.

Metastatic Setting

COSMIC-313

The phase 3 COSMIC-313 trial (NCT03937219) is evaluating the combination of cabozantinib (Cabometyx), nivolumab (Opdivo), and ipilimumab (Yervoy) in patients with RCC with variant histologies.⁵ While the PFS results in COSMIC-313 were significantly better with the triplet combination vs doublet therapy, experts explain that the harms outweigh the benefits. With the triplet therapy, grade 3-4 AEs, dose reductions, treatment discontinuations, and the need for high-dose steroids were significantly higher.

“We experienced firsthand at our center an increased rate of toxicity with the triplet therapy and that was reported in the results. With the triplet, we had 73% vs 41% grade 3 or 4 treatment-related adverse events. That is a consideration for these patients in the metastatic setting and how that's going to affect their quality of life,” said Jackson-Spence.

RENOTORCH

In the metastatic setting, there is exciting data from RENOTORCH (NCT04394975), a phase 3 study in intermediate-/poor-risk unresectable or metastatic RCC.^6,7 In this study, toripalimab plus axitinib (Inlyta) led to longer PFS rates and a higher overall response rate vs sunitinib (Sutent) in this patient population. The combination also had a manageable safety profile.

At a median follow-up of 14.6 months, the median PFS was 18.0 months with toripalimab and axitinib vs 9.8 months with sunitinib (HR, 0.65; 95% CI, 0.49-0.86; P =.0028). At 12 months, the PFS rate was 62.7% with toripalimab/axitinib and 45.4% with sunitinib, and at 24 months, rates were 44.6% and 30.2%, respectively. Other findings showed that the complete response rate was 4.8% vs 3.8% in the toripalimab/axitinib vs sunitinib arms, respectively, and the partial response rates were 51.9% and 27.0% (P <.0001). In the toripalimab/axitinib arm, the median duration of response was not reached vs 16.7 months in the sunitinib arm (HR, 0.614; 95% CI, 0.340-1.137). Preliminary results also showed that the median OS was not reached with toripalimab and axitinib vs 26.8 months with sunitinib (HR, 0.61; 95% CI, 0.40-0.92; P =.0186).

“I think immunotherapy has been the cornerstone for frontline management for the majority of patients. It's really changed the landscape of treatments there,” said Young.

Conceptual image for prostate cancer treatment, 3D illustration showing destruction of a tumor inside prostate gland: © Dr_Microbe - stock.adobe.com

Prostate Cancer

“Prostate cancer has been somewhat unique in its development. It has not benefited from immunotherapy in a similar fashion as other solid tumor cancers, and because of that, it has somewhat stalled in terms of significant advancements when you compare it to other tumors,” said Young.

Still, there have been interesting trials that have come out in the past 2 years or so, including the use of triplet therapy in the ARASENS trial (NCT02799602).⁸

ARASENS

The phase 3 ARASENS study showed that among patients with metastatic, hormone-sensitive prostate cancer, the combination of darolutamide (Nubeqa), androgen-deprivation therapy, and docetaxel led to significantly longer OS vs placebo plus androgen-deprivation therapy and docetaxel. The frequency of AEs between the 2 groups was similar.

“The outcomes of those studies suggest that patients who have high-volume disease might benefit from triplet therapy compared to sequential. It looks like using all 3 upfront is better than using them sequentially,” said Young.

VISION

Another area of prostate cancer gaining attention is the use of radionuclide treatments. Specifically, the VISION trial (NCT03511664) looked at ¹⁷⁷Lu-PSMA-617 (Pluvicto), compared with physicians’ choice of treatment, in patients who had heavily treated prostate cancer.⁹ In March 2022, the findings supported the FDA approval of ¹⁷⁷Lu-PSMA-617 for the treatment of patients with PSMA-positive metastatic castration-resistant prostate cancer who have received treatment with an androgen receptor pathway inhibitor and taxane-based chemotherapy.

“There is data more recently presented as well, looking at lutetium in earlier phases, which again, holds promise that there might be merit for looking at further studies using radionuclides. I do think the prostate [space] has not had quite the same level of advancement as other solid tumors, so there's an ongoing need to try to improve survival and outcomes in those patients,” added Young.

Moving Forward

The horizon for GU cancers has expanded and the treatment landscape continues to rapidly evolve. These updates provide only a glimpse at the full picture of the promising breakthroughs in this field.

With the 2024 ASCO GU Symposium just around the corner, the stage is set for a flood of new data and clinical trial results that will undoubtedly shape the future of how oncologists treat these urologic cancers.

REFERENCES:

1. Powles TB, Perez Valderrama B, Gupta S, et al. LBA6 EV-302/keynote-A39: Open-label, Randomized Phase III study of enfortumab vedotin in combination with Pembrolizumab (EV+P) vs Chemotherapy (chemo) in previously untreated locally advanced metastatic urothelial carcinoma (LA/MUC). Annals of Oncology. 2023;34. doi:10.1016/j.annonc.2023.10.106

2. Sheng X, Zhou L, Yang K, et al. Disitamab vedotin, a novel humanized anti-HER2 antibody-drug conjugate (ADC), combined with toripalimab in patients with locally advanced or metastatic urothelial carcinoma: An open-label phase 1b/2 study. J Clin Oncol 41, 2023 (suppl 16; abstr 4566). doi: 10.1200/JCO.2023.41.16_suppl.4566

3. Petrylak DP, Tagawa ST, Jain RK, et al. Primary analysis of TROPHY-U-01 cohort 2, a phase 2 study of sacituzumab govitecan (SG) in platinum (PT)-ineligible patients (pts) with metastatic urothelial cancer (mUC) that progressed after prior checkpoint inhibitor (CPI) therapy. J Clin Oncol. 2023;41(suppl 6):520. doi:10.1200/JCO.2023.41.6_suppl.520

4. Choueiri TK, Tomczak P, Park SH, et al. Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma. N Engl J Med. 2021;385(8):683-694. doi:10.1056/NEJMoa2106391

5. Go C, Okumura H, Miura Y. Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma. N Engl J Med. 2023;389(5):477. doi:10.1056/NEJMc2306786

6. Yan XQ, Ye MJ, Zou Q, et al. Toripalimab plus axitinib versus sunitinib as first-line treatment for advanced renal cell carcinoma: RENOTORCH, a randomized, open-label, phase III study. Ann Oncol. Published online October 20, 2023. doi:10.1016/j.annonc.2023.09.3108

7. Yan X, Ye M, Zou Q, et al. Toripalimab plus axitinib versus sunitinib as first-line treatment of advanced renal cell carcinoma: RENOTORCH, a randomized, open-label, phase III study. Ann Oncol. Published online October 21, 2023. doi:10.1016/j.annonc.2023.09.3108

8. Smith MR, Hussain M, Saad F, et al. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. N Engl J Med. 2022;386(12):1132-1142. doi:10.1056/NEJMoa2119115

9. Rohith G. VISION trial: 177Lu-PSMA-617 for progressive metastatic castration-resistant prostate cancer. Indian J Urol. 2021;37(4):372-373. doi:10.4103/iju.iju_292_21