Updated Clinical Trial Data Reflect Efforts to Optimize IO Combos in Non-ccRCC and MIBC, Fine-Tune ADT-Based Regimens in Prostate Cancer

In an interview with OncLive®, Pedro Barata, MD, highlighted and expanded upon key updates in immuno-oncology (IO) discussed by his colleagues at a recent State of the Science Summit on genitourinary cancer, which he chaired.

These included ongoing efforts to refine the use of IO/TKI combinations in non–clear cell renal cell carcinoma (RCC), the role of perioperative checkpoint inhibition in muscle-invasive bladder cancer (MIBC) according to updated data from the phase 3 NIAGARA trial (NCT03732677), and implications from the phase 3 ARANOTE trial (NCT04736199) for the continued evaluation of androgen receptor pathway inhibitors (ARPIs) as a standard addition to androgen deprivation therapy (ADT) in metastatic hormone-sensitive prostate cancer (mHSPC).

In a concurrent interview, Barata also highlighted efforts to identify the role of current radioligand therapies, develop novel targets beyond prostate-specific membrane antigen (PSMA), and shift towards biomarker-driven strategies in prostate cancer.

Barata is the director of the Clinical Genitourinary Medical Oncology Research Program at University Hospitals Seidman Cancer Center, the Miggo Family Chair in Cancer Research at University Hospitals, and an associate professor of medicine at Case Western Reserve University School of Medicine in Cleveland, Ohio.

OncLive: According to the presentation given by your colleague Jason Brown MD, PhD, of University Hospitals Seidman Cancer Center, what efforts are ongoing to refine the use of IO/TKI combinations in rarer non–clear cell RCC subtypes?

Barata: IO/TKIs are playing a major role for patients with many different types of non–clear cell RCC, and that seems to be aligned with what folks are starting to do in clinical practice. Yet there’s a need for larger, randomized level 1 studies, and those studies are ongoing. Several different trials are exploring or comparing novel combinations against the standard of care [SOC] thus far. [Dr Brown] also reminded us how important chemotherapy can be for particular tumors, such as collecting duct RCC, and highlighted real-world data with these different IO-based approaches for the different non–clear cell RCC subtypes.

As discussed by Mehmet Asim Bilen, MD, of Winship Cancer Institute at Emory University, what current data inform the selection of frontline IO-based regimens in advanced clear cell RCC, and how does the absence of clear biomarkers affect this decision-making?

Dr Bilen did a great job summarizing the data on the different IO-based combinations out there. [In clear cell RCC] we lack a clear biomarker to help us [determine] whether we should [select] an IO [approach alone] or an IO/TKI regimen. Data from the [phase 3] CLEAR [NCT02811861] and KEYNOTE-426 [NCT02853331] studies [were discussed to illustrate] that point, as we don’t see RNA sequencing data supporting the use of a particular combination. He also reminded us of what to do upon progression and did a good job highlighting what therapies are available.

Finally, [we discussed] real-world efforts to [determine if] patients are being treated similarly beyond or off clinical trials as [they are] treated on trials. [These investigations are] focusing on durable responders vs rapid progressors.

What are some next steps and potential implications for the investigation of darolutamide (Nubeqa) plus ADT in mHSPC, per updated data from the ARANOTE trial?

In his prostate cancer talk, Dr Bilen summarized the data for mHSPC, focusing on the ARANOTE trial. ARANOTE is the most recent of the large phase 3 trials demonstrating the benefit of adding an ARPI to standard ADT. He provided the data for all those different ARPIs, including abiraterone acetate [Zytiga], enzalutamide [Xtandi], and apalutamide, with or without docetaxel for abiraterone acetate and darolutamide [Nubeqa]. The ARANOTE trial, not surprisingly, showed benefit with adding darolutamide to ADT alone [according to a presentation from the 2024 ESMO Congress]. Of course, in the United States [US], patients do have access to ARPIs. Randomly assigning them to ADT alone would no longer be acceptable, so this trial was [modeled after an ex-US paradigm].

Then we have the phase 2 ARASEC trial [NCT05059236], which will [complement] the ARANOTE data, and we’ll see if [the regimen] ends up getting approved by regulatory agencies. I predict that it will. There’s no reason for us to think that [that regimen is] not at least similarly efficacious [compared with] other ARPIs out there. However, [these ARPIs] seem to have different safety profiles, [which] perhaps favor darolutamide to some extent. We’ve seen [those safety] data from the metastatic castration-resistant prostate cancer setting. The question is, do patients do better on darolutamide compared with apalutamide, enzalutamide, or abiraterone acetate? I don’t think we have a clear answer yet. As longer follow-up data become available, we’ll see if [this darolutamide regimen] ends up showing a survival advantage, and how the regulatory agency [interprets] those data.

Based on the presentation given by Shilpa Gupta, MD, of Cleveland Clinic, what are the implications of findings from the NIAGARA trial for MIBC? How might the anticipated FDA approval of perioperative durvalumab (Imfinzi) plus neoadjuvant chemotherapy change the treatment paradigm?

Dr Gupta did a great job highlighting the data in the perioperative setting for patients with MIBC, reminding us of the data around radical cystectomy and adjuvant immunotherapy. [She also provided an] overview of the different checkpoint inhibitors available in that setting, [reviewing the data from the phase 3] AMBASSADORAlliance A031501 trial [NCT03244384] investigating pembrolizumab [Keytruda] and the [phase 3] CheckMate 274 study [(NCT02632409) evaluating nivolumab (Opdivo)].

From that point of view, the most recent data [on checkpoint inhibition] to be presented were from the NIAGARA trial, [which evaluated neoadjuvant durvalumab plus] gemcitabine and cisplatin followed by durvalumab in the adjuvant setting [for cisplatin-eligible patients]. [At the State of the Science Summit], we went through the disease-free survival and overall survival advantage [conferred with this regimen over neoadjuvant cisplatin-based chemotherapy alone]. [This trial is] practice changing; [in fact], it was presented at a session called practice-changing trials at the 2024 ESMO Congress.

[However], there are still debates about the best strategy [in MIBC]. In that trial, the comparator was a non-IO approach, including in the adjuvant setting. We do have nivolumab, which is a SOC for patients with residual disease after radical cystectomy, and eligibility is different depending on [whether a patient has] received prior neoadjuvant chemotherapy. The jury is still out from that perspective. There’s no doubt in my mind that this is going to be incorporated into the guidelines [in MIBC], but we’ll see what the regulatory agency is going to do. It sounds like, based on Dr Gupta’s comments, that people are already using [perioperative durvalumab], along with the other option [of utilizing a] cisplatin-containing regimen, followed by nivolumab in an adjuvant setting for patients with residual disease, depending on the use of prior chemotherapy. These are important data to highlight and contextualize in nonmetastatic MIBC.