Based on the findings of the phase III VISION trial, reported by Sartor et al¹ and summarized in this issue of The ASCO Post, lutetium-177–PSMA-617 (LuPSMA) is the first of the prostate-specific membrane antigen–targeted cancer theranostics to demonstrate a survival-prolonging benefit for men with metastatic castration-resistant prostate cancer. The treatment options currently available for men with metastatic castration-resistant prostate cancer who have experienced disease progression despite an androgen receptor (AR)-signaling inhibitor, docetaxel, and cabazitaxel are limited by cross-resistance (alternate AR-signaling inhibitor) and low anticancer response rates (radium-223). Owing to its robust anticancer activity, new mechanism of action, and excellent tolerability, LuPSMA is poised to become the preferred treatment for prostate cancer that is refractory to AR-signaling inhibitors and taxanes.

Deciding Between LuPSMA and Cabazitaxel

Given the recently published CARD trial affirming the overall survival benefit for cabazitaxel relative to an alternative AR-signaling inhibitor,² the decision between LuPSMA and cabazitaxel will remain an area of controversy, given that VISION did not compare these options. Notably, TheraP,³ a recently published randomized phase II trial comparing LuPSMA with cabazitaxel found that the radioligand led to a dramatically higher prostate-specific antigen and soft-tissue response rate compared with cabazitaxel. However, important differences in patient selection between TheraP and VISION, particularly in regard to PSMA positron-emission tomography (PET), need to be understood to best guide this clinical decision.

Lutetium-177–PSMA-617 is the first of the PSMA-targeted cancer theranostics to demonstrate a survival-prolonging benefit for men with metastatic castration-resistant prostate cancer.

— David R. Wise, MD, PhD

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A minimum standardized uptake value for PSMA on PET imaging will likely be required as a pretreatment biomarker for LuPSMA treatment. The VISION trial purposefully liberalized the PSMA entry criteria, allowing any PSMA standardized uptake value above background for study entry. By contrast, TheraP required higher PSMA standardized uptake values on PET than required for VISION and excluded patients with PSMA-negative lesions that were fluorodeoxyglucose avid on PET scan.

Consequently, for patients with high and uniform PSMA uptake, ­LuPSMA rather than cabazitaxel would be expected to be the superior option, as in TheraP. By contrast, the optimal choice between cabazitaxel and LuPSMA for patients with modest and/or patchy PSMA uptake remains unknown and will need to take into account the patient’s fitness for cabazitaxel, the relative PSMA uptake, and clinical urgency for treatment response. Retrospective analysis of VISION and TheraP focused on PSMA PET standardized uptake values, and a recently published nomogram⁴ correlating clinical benefit from LuPSMA with the intensity of PSMA uptake will further guide this treatment decision.

On the Horizon

Will the use of LuPSMA earlier in the disease course lead to an improvement in the durability of response? Two ongoing phase III studies will address this question: PSMAfore (ClinicalTrials.gov identifier NCT04689828) for second-line predocetaxel metastatic castration-resistant prostate cancer and PSMAddition (NCT04720157) for first-line treatment of hormone-sensitive metastatic prostate cancer added to the standard of care. The results of these studies could hinge on whether the anticancer effectiveness of LuPSMA will outweigh the risks posed by cumulative late bone marrow and renal toxicity.

Improving the durability of response to LuPSMA will also require a better understanding of the dominant mechanisms of resistance to this therapy. Intensive efforts are currently focused on two key mechanisms: (1) defects in the cellular DNA damage response and (2) evolution to PSMA-negative (neuroendocrine or non-neuroendocrine/AR-negative) prostate cancer. These efforts could pave the way for clinical trials of novel combinations targeting these ­mechanisms.

Take-Home Message

VISION is a practice-changing trial that demonstrated a survival benefit for LuPSMA in patients with metastatic castration-resistant prostate cancer. Key implementation questions remain, but the use of this agent will likely serve as a cornerstone of future combination regimens and signals the arrival of theranostics to prostate cancer. 

Dr. Wise works at NYU Langone Health, Perlmutter Cancer Center, New York.

DISCLOSURE: Dr. Wise has received honoraria from OncLive; has served as a consultant to Alphasights, Aptitude Health, Foundation Medicine, Guidepoint, GLG, Janssen, Leap Therapeutics, Pfizer, and Silverlight; and has been reimbursed for travel, accommodations, or other expenses by Pfizer.

REFERENCES

1. Sartor O, de Bono J, Chi KN, et al: Lutetium-177–PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. June 23, 2021 (early release online).

2. de Wit R, de Bono J, Sternberg CN, et al: Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer. N Engl J Med 381:2506-2518, 2019.

3. Hofman MS, Emmett L, Sandhu S, et al: [177Lu] Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): A randomised, open-label, phase 2 trial. Lancet 397:797-804, 2021.

4. Gafita A, Calais J, Grogan TR, et al: Nomograms to predict outcomes after 177Lu-PSMA therapy in men with metastatic castration-resistant prostate cancer: An international, multicentre, retrospective study. Lancet Oncol. July 8, 2021 (early release online).