AUA 2022: Update on Clinical Trials in Prostate Cancer

(UroToday.com) In a podium presentation at the 2022 Society of Urologic Oncology Meeting held in conjunction with the American Urologic Association Annual Meeting held in New Orleans and virtually, Dr. Sartor provided an update on important clinical trials in advanced prostate cancer. He grouped this approach to this question three categories: the first, focusing on the role of PSMA-PET imaging which he described as disrupting staging in a huge way, treatment advances in hormone sensitive prostate cancer, and treatment advances in castration-resistant prostate cancer.


He began by emphasizing that the treatment landscape of advanced prostate cancer will be reshaped with increased utilization of PSMA-based imaging. He began giving some background on PSMA, highlighting that this is a transmembrane protein with a large extracellular domain which may be targeted for imaging and therapeutic purposes.

AUA22_Sartor_0

Already, the use of PSMA-PET molecular imaging has been a disruptive force across the spectrum of the natural history of prostate cancer. To date, we have seen approvals for PSMA-based imaging approaches in the primary staging of patients with high-risk disease, in the biochemical recurrence setting, and prior to theranostic treatment with Lu-177-PSMA. In doing so, PSMA-based molecular imaging is redefining staging for these patients given its higher sensitivity and accuracy for the detection and localization of disease.

Moving into treatment approaches, Dr. Sartor emphasized that treatment approaches are rapidly evolving across the spectrum of prostate cancer. In particular, there is a trend for early use of agents with proven benefit in later lines. So far, this has manifest with earlier utilization of novel hormonal agents earlier and earlier in the disease trajectory.

AUA22_Sartor_1

In the metastatic hormone sensitive space (mCSPC), he emphasized that there are many treatment approaches with proven overall survival benefits including docetaxel (CHAARTED and STAMPEDE), abiraterone (LATITUDE and STAMPEDE), enzalutamide (ENZAMET and ARCHES), and apalutamide (TITAN). Further, in the past year, we have seen new data emerging from both PEACE-1 and ARASENS in the metastatic space and from STAMPEDE in the non-metastatic space. Beginning first with PEACE-1, Dr. Sartor highlighted that this 2x2 factorial randomized trial examined both the role of abiraterone as systemic treatment intensification and local radiotherapy as primary tumor intensification among patients with de novo mCSPC. Notably, the standard of care changed during the course of this trial such that many patients received concurrent docetaxel. Based on data initially presented at ESMO and subsequently published, the addition of abiraterone to standard of care was associated with improved radiographic progression-free survival and overall survival. Notably, as with some prior trials, the effect was particularly pronounced in the high-volume subset of patients, with an attenuated effect in those with low-volume disease though these data remain immature. He noted that, based on a comparison from Dr. Fizazi at ESMO, that the triplet approach was associated with longer overall survival in the high-volume subset than either approach alone, though cross-trial comparisons have their intrinsic limitations.

Dr. Sartor suggested that there are clearly impressive PFS results with the triplet approach with a clear suggestion of benefit in overall survival among patients with high-volume disease. However, there are no trials comprising ADT and abiraterone with or without docetaxel. Further, we must consider the data from ARASENS. As a result, he suggested that triplet approach may be best used in the young, fit patient.

Building on these data, he discussed the recent publication of the ARASENS data examining the triplet combination of darolutamide, docetaxel, and ADT compared to docetaxel and ADT. This demonstrated a statistically significant survival benefit to the combination arm, with landmark survival of 62.7% at 4 years. The triplet approach had further benefits in terms of time to castration resistant disease and pain progression. Further, in terms of time adjusted adverse events, this approach was well tolerated. Thus, Dr. Sartor concluded that these data are consistent with that from PEACE-1. However, the remaining question is how much additional value is derived from the addition of docetaxel to ADT and a novel hormonal treatment.

Moving disease states somewhat, Dr. Sartor discussed recently presented data from the STAMPEDE trial examining the role of abiraterone in high-risk non-metastatic disease. The vast majority of these patients were newly diagnosed and had either nodal involvement or high-risk characteristics (cT3/4, PSA>40ng/mL, or Gleason 8, 9, 10). He emphasized that these data really represent the meta-analysis of two trials that were joined after the combination of abiraterone and enzalutamide was found to be no better than abiraterone alone. With no difference between them (interaction p=0.908), these studies found that treatment intensification was associated with a significant 46-47% improved metastasis-free survival. In terms of landmark 6-year overall survival, this translates to an improvement from 69% to 82%. Similarly, there were significant improvements in overall survival from 77% to 86% at 6-years, a 40% relative reduction in the risk of death. Dr. Sartor characterized this as a “clearly positive” study in the “super high risk” non-metastatic subset. Thus, this builds on the available data that earlier use of abiraterone improved outcomes. However, the lack of PSMA-based staging is somewhat problematic as many of these patients would have metastatic disease on PSMA-PET.

Moving forward in mHSPC, he highlighted four trials that between them will have important implications for understanding the role of Lu-PSMA and of combination therapy including novel hormonal agents with immune checkpoint inhibitors, PTEN targeted therapeutics, and PARP inhibitors in this disease space.

AUA22_Sartor_3

He then transitioned to a discussion of treatment advances in mCRPC. In this context, he highlighted the evolution of treatment approaches over the past 15 years beginning with TAX-327 in the front-line setting and including further lines of therapy. As highlighted in the figure below, each of these trials has provided a relatively modest 2.4 to 4.8 month overall survival benefit though they have each become part of our standard of care.

AUA22_Sartor_4 

Dr. Sartor then addressed the question of whether we should be using combination treatment approaches as standard of care concluding that, thus far, there are not though some combinations do deserve further scrutiny. First, he highlighted data from the PROpel trial in which patients with previously untreated mCRPC were randomized to first-line olaparib with abiraterone or abiraterone alone. Notably, homologous recombination repair status was determined retrospectively in this study. As reported at ASCO-GU, this was a positive study with a statistically significant improvement in radiographic progression-free survival. Notably, subgroup analyses demonstrated no statistically significant difference in effect on the basis of homologous recombination repair status though the magnitude of effect was quantitatively larger among those with HRR mutations.

In terms of toxicity, DR. Sartor highlighted that the PROpel trial demonstrated increased anemia XXXXXadd hereXXXXXXX. Summarizing the data from PROpel, he suggested that these data of first-line treatment in mCRPC suggest that the combination approach with abiraterone and olaparib has better radiographic progression-free survival than abiraterone alone, with a greater effect among patients with HRR mutations. However, overall survival data are immature to date.

He then moved to discussing PSMA-targeted therapies. As others have alluded to, a PSMA-binding molecule may be linked to a number of therapeutic payloads, including Lu-177 or Ac-225.

Citing relatively early data published by Rahbar and colleagues in 2017, he noted relatively promising results with the treatment regime of 177Lu-PSMA-617 at a time when optimal dose and schedule had not yet been established. This therapeutic paradigm was more fulsomely tested in the phase III VISION trial which, as he noted, led to FDA approval as of March 23, 2022. This pivotal phase III trial enrolled patients with mCRPC who had received at least one novel hormonal agent and at least one taxane. Notably, they had to have evidence of PSMA avid disease on PSMA-PET/CT, but FDG PET was not mandated. Patients were randomized 2:1 to 177Lu-PSMA-617 or best standard of care. He noted that approximately 13% of potentially eligible patients did not meet the PSMA eligibility criteria and were therefore excluded.

AUA22_Sartor_6 

VISION met both co-primary endpoints demonstrating significant improvements in overall survival (38% risk reduction in death) and radiographic progression-free survival (60% risk reduction for progression/death).

AUA22_Sartor_7 

Among secondary endpoints, treatment with 177Lu-PSMA-617 was associated with higher response rates among those with measurable disease, higher PSA response rates, and higher complete response rates. Moving forward, he highlighted three trials (as listed below) that will continue to refine the role of 177Lu-PSMA therapy in mCRPC.

AUA22_Sartor_8 

He further noted other rials that are examining novel treatment paradigms in this disease space including targeted therapies and immune checkpoint inhibitors.

AUA22_Sartor_9 

Presented by: Oliver Sartor, MD, Tulane Medical School