Standards of Care Shift Toward Patient Specificities in Bladder and Prostate Cancers

Shilpa Gupta, MD

The future looks bright for the treatment of urothelial carcinoma in the frontline setting and beyond, ushered in by a collection of successful clinical trial readouts that may deepen the efficacy of personalized treatment sequencing, according to Shilpa Gupta, MD. Additionally, advances in prostate cancer diagnosis and treatment are arising with the use of increasingly sensitive PSMA PET scans that guide therapeutic decisions.

“As the current treatment options [in bladder cancer], platinum chemotherapies still remain the backbone of frontline therapy. Single-agent immunotherapy should only be used in select patients who are platinum ineligible. Avelumab [Bavencio] maintenance should be used after the use of platinum chemotherapy if patients don’t progress,” Gupta said following an OncLive^® State of the Science Summit™ on bladder and prostate cancer, which she chaired.

In an interview with OncLive^®, Gupta discussed key insights from the meeting, including potential therapies for patients with cisplatin-ineligible metastatic urothelial carcinoma, the benefits of sacituzumab govitecan-hziy (Trodelvy) and erdafitinib (Balversa) in later-line urothelial carcinoma, treatment options for nonmetastatic castration-resistant prostate cancer (CRPC), when stereotactic body radiation therapy (SBRT) may be avoided in oligometastatic prostate cancer, and survival data with enzalutamide (Xtandi) plus androgen deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (HSPC).

Gupta is the director of Genitourinary Medical Oncology at Taussig Cancer Institute and co-leader of the Genitourinary Oncology Program in the Department of Hematology and Medical Oncology at Cleveland Clinic in Cleveland, Ohio.

OncLive^®: Could you summarize your presentation on the first-line treatment of metastatic urothelial carcinoma?

Gupta: I reviewed frontline treatment strategies in metastatic urothelial cancer, the current standard of care, and future prospects. I discussed how [platinum-based regimens] are still the backbone of frontline therapy in metastatic urothelial cancer.

Gemcitabine plus cisplatin and dose-dense MVAC [methotrexate, vinblastine sulfate, doxorubicin hydrochloride, and cisplatin] have resulted in median overall survivals [OS] of 14 to 15 months, with response rates between 50% and 70%. Additionally, in recent contemporary trials, gemcitabine plus carboplatin has shown response rates around 43%.

Only a minority of patients receive second-line therapy, so there’s an unmet need to improve survival with frontline therapy. The way we assess for treatment selection for the first-line setting is based on whether the patient is cisplatin eligible. If the patient is cisplatin eligible, then we want to offer cisplatin-based chemotherapy followed by avelumab maintenance if they do not progress after [the chemotherapy]. If the patient is cisplatin ineligible and can get gemcitabine and carboplatin, we should offer gemcitabine plus carboplatin followed by avelumab maintenance.

Only about a handful of patients, less than 10%, are truly platinum ineligible. In those cases, we could use atezolizumab [Tecentriq] or pembrolizumab [Keytruda]. Otherwise, the standard of care should be to use gemcitabine plus carboplatin followed by avelumab maintenance.

I also talked about some recent work showing that cisplatin-ineligible patients with a tumor mutational burden [TMB] higher than 10 can do better with single-agent immunotherapy compared with gemcitabine plus carboplatin. These are all retrospective data using the FoundationOne® and Flatiron Health databases, but they are consistent with what we saw in frontline [phase 3] trials like KEYNOTE-361 [NCT02853305], IMvigor130 [NCT02807636], and DANUBE [NCT02516241]. PD-L1 has not panned out as a solid biomarker, but TMB looks to be a more promising biomarker.

[I also discussed] defining platinum ineligibility with the label restrictions for the use of pembrolizumab and atezolizumab back in 2018. More recently, the FDA only restricted pembrolizumab use to patients who are not platinum eligible at all, regardless of PD-L1 expression.

We first took on this endeavor to define platinum ineligibility by creating a bladder cancer working group. Now, we have updated the criteria we had first presented in 2019, given that there were so many treatment landscape changes.

Based on our survey of around 60 medical oncologists who treat bladder cancer in the United States, we came up with some guiding factors like [ECOG] performance status of 3 or higher, creatinine clearance less than 30 mL/min, grade 2 or higher peripheral neuropathy, and significant heart failure. These criteria could help us decide whether to give carboplatin, so patients are not [overlooked] for platinum ineligibility, as single-agent immunotherapy doesn’t work as well as gemcitabine plus carboplatin.

I also reviewed that the frontline KEYNOTE-361 and IMvigor130 trials were negative for chemoimmunotherapy combinations compared with [platinum-based chemotherapy] alone. OS and progression-free survival were not improved in KEYNOTE-361, and we are still waiting for OS updates for IMvigor130. Frontline immunotherapy doublets like durvalumab [Imfinzi] plus tremelimumab also did not perform better than gemcitabine plus cisplatin or gemcitabine plus carboplatin in the DANUBE trial.

In the [phase 3] CheckMate901 trial [NCT03036098], where ipilimumab [Yervoy] and nivolumab [Opdivo] are being compared with gemcitabine plus cisplatin or gemcitabine plus carboplatin plus nivolumab or just platinum chemotherapies alone, a press release [stated] that for patients with high PD-L1 expression, immunotherapy was not better than platinum chemotherapy. We’re still waiting for the full data.

I also looked at the [phase 3] JAVELIN Bladder 100 study [NCT02603432], which is the pivotal switch maintenance trial that set the standard of care to avelumab and best supportive care [BSC]. In that trial, avelumab was significantly better than BSC alone in patients who did not progress on gemcitabine plus cisplatin treatment. The updated median follow-up of at least 38 months showed that the OS with avelumab [in all patients] was 23.8 months compared with 15.0 months with BSC.

I talked about the rationale of trying to intensify the avelumab backbone and how the VEGF TKI cabozantinib [Cabometyx] might be a good partner based on the preclinical and clinical rationale of the combination of cabozantinib and other checkpoint inhibitors.

Additionally, I discussed the phase 3 trial I’m leading through the [Alliance for Clinical Trials in Oncology], the phase 3 MAIN-CAV trial [NCT05092958], where patients who receive frontline platinum chemotherapy and do not progress are randomized to avelumab for up to 2 years vs cabozantinib and avelumab. The primary endpoint is OS. We want to see if adding cabozantinib to avelumab will further push the envelope and improve survival in our patients.

I also reviewed the recent data that were presented at the 2022 ESMO Congress by Jonathan E. Rosenberg, [MD, of Memorial Sloan Kettering Cancer Center in New York, New York,] for cohort K of the [phase 1/2] EV-103 study [NCT03288545]. Earlier work with Christopher J. Hoimes, [DO, of Duke Cancer Institute in Durham, North Carolina,] Dr Rosenberg, and others was published, where, in the EV-103 cisplatin-ineligible patient cohort, the combination of enfortumab vedotin-ejfv [Padcev] and pembrolizumab had shown remarkable activity and promising OS. That was a single-arm cohort.

Cohort K randomized patients to enfortumab vedotin vs enfortumab vedotin and pembrolizumab in cisplatin-ineligible patients. In the 76 patients [who received enfortumab vedotin plus pembrolizumab], the combination resulted in a 64.5% response rate compared with 45.2% with enfortumab vedotin monotherapy. The survival data are not mature. Toxicity was much higher with the combination, so the efficacy came at the price of toxicity.

The ongoing EV-302 study [NCT04223856] is the randomized phase 3 trial looking at enfortumab vedotin and pembrolizumab vs gemcitabine plus cisplatin or gemcitabine plus carboplatin. These patients in the enfortumab vedotin plus pembrolizumab arm continue pembrolizumab for up to 2 years, and there is no stop date for enfortumab vedotin. In the control arm, patients are allowed to get maintenance immunotherapy if they qualify for that. These are all exciting data that we are looking forward to. EV-302 is wrapping up enrollment, and we’ll see more data coming out.

I also reviewed some upcoming combinations like erdafitinib and cetrelimab [JNJ-63723283] in frontline cisplatin-ineligible patients in the [phase 1b/2] NORSE study [NCT03473743]. Those are small numbers, but the combination in the FGFR-selected patients was better than single-agent erdafitinib.

The [combination of the] antibody-drug conjugate [ADC] enfortumab vedotin and pembrolizumab could move up to the cisplatin-ineligible frontline patient population, but the ultimate litmus test will be the EV-302 readout.

In conclusion, we need biomarkers to better personalize first-line therapy. That ongoing work will help us understand how to complement patients’ clinical conditions with biomarkers to offer the most personalized therapy.

Your colleague, Moshe Ornstein, MD, MA, of Cleveland Clinic, presented on second- and later-line management in metastatic urothelial carcinoma. What novel agents beyond chemotherapy and immunotherapy are arising for refractory patients? How might these agents fit into the treatment paradigm going forward?

Besides enfortumab vedotin, there’s another ADC, sacituzumab govitecan, which showed promising activity in the [phase 2] TROPHY-U-01 study [NCT03547973]. In that trial, the drug showed activity even in patients who received prior enfortumab vedotin, although that was a small number. The overall response rate was 27%, which was quite promising.

The ongoing [phase 3] TROPiCS-04 study [NCT04527991] will address this question, where patients who have progressed on prior platinum chemotherapy and immunotherapy are randomized to sacituzumab govitecan or physician’s choice of salvage chemotherapy. The primary end point is OS. In the meantime, the FDA has given accelerated approval for use of this agent after patients have had prior platinum chemotherapy, immunotherapy, and enfortumab vedotin.

Sacituzumab govitecan is a reasonable option in the treatment landscape, and the toxicities are not overlapping with enfortumab vedotin. With enfortumab vedotin, the key toxicities are significant peripheral neuropathy, rash, and diabetes. With sacituzumab govitecan, they’re primarily neutropenia and diarrhea, which we can preemptively manage.

Depending on where a patient’s comorbidities lie, we can think of sequencing, whether we use sacituzumab govitecan first or after enfortumab vedotin. [Dr Ornstein touched upon] erdafitinib for patients who have FGFR select mutations or fusions. In the real world, the occurrence of such mutations or fusions is 10% to 15%, but those patients can take erdafitinib.

The sequence is not yet defined, so depending on patient preferences and prior toxicities from prior treatments, we could choose whether to use erdafitinib, enfortumab vedotin, or sacituzumab govitecan first. The goal is to be able to offer all these therapies at some point in a patient’s journey.

[Dr Ornstein also talked about] several ongoing trials and the [benefits of] sequencing trials to better guide treatment options. For the current scenario, [the standard of care is] platinum chemotherapy followed by avelumab maintenance if patients are not progressing. If they are progressing, then [we switch to] pembrolizumab, and if they progress further, then [we use] ADCs and FGFR inhibitors.

Christopher Wee, MD, of Cleveland Clinic, presented on the management of nonmetastatic CRPC. How might the 3 National Comprehensive Cancer Network-recommended agents, apalutamide (Erleada), enzalutamide, and darolutamide (Nubeqa) fit into the treatment paradigm for this disease?

These are all in the same class of agents, androgen receptor inhibitors. The discussion of all the studies was that there’s a delay to the development of metastatic disease, but we should carefully weigh whether patients need these treatments or if we could follow them on just ADT if their prostate-specific antigen doubling time is less than 10 months.

Biomarkers will help us define this, and especially in the era of PSMA PET scans, [nonmetastatic disease] is a shrinking area. [In the future,] we may not have many nonmetastatic patients because the PSMA PET is so sensitive at picking up subtle disease.

This was a great discussion on what options we have and, toxicity-wise, which agents we could use, depending on patients’ toxicity tolerances and comorbidities. For example, with apalutamide, the main toxicity is rash, but [the drug is] otherwise well tolerated. Enzalutamide can have more significant toxicity compared with darolutamide or apalutamide. Darolutamide has the most favorable toxicity profile.

Regarding the presentation Omar Mian, MD, PhD, of Cleveland Clinic, gave on the emerging role of SBRT in oligometastatic prostate cancer, what are the benefits of PSMA PET technology when guiding SBRT?

Dr Mian gave a nice overview of emerging data with SBRT in patients with oligometastatic hormone-sensitive disease. PSMA PET is especially useful in that setting because although a conventional scan might deem a patient oligometastatic, having only 3 or 4 lesions, for example, a PSMA PET could show that that same patient may have even more disseminated disease, and then that patient would not be a great candidate for SBRT. If patients have high disease volume and a high number of metastatic sites, then SBRT is not a feasible option. That is the key role [of PSMA PET].

Dr Mian also reviewed the work done at Tata Memorial Hospital in Mumbai, India, where, using PSMA PET, they decided whether to offer pelvic nodal radiation. Those are the studies where we are seeing when PSMA PET can be a useful guide.

Jorge A. Garcia, MD, FACP, of Case Comprehensive Cancer Center, gave a presentation focused on advances in metastatic HSPC. In the phase 3 ARCHES trial (NCT02677896), what survival benefits were seen with enzalutamide plus ADT in patients who had received prior ADT?

In the ARCHES trial, the addition of enzalutamide to ADT reduced the risk of death in patients with metastatic HSPC by 34% vs placebo plus ADT. With longer follow-up, the investigators showed that the survival benefit with enzalutamide became more apparent.