Oncology
Metastatic Prostate Cancer
Prostate-Specific Membrane Antigen–Targeted Therapies: Expert Insights
Overview
Prostate-specific membrane antigen (PSMA) has emerged as a preeminent prostate cancer target for diagnostic imaging. Additionally, as seen at the 2021 Genitourinary Cancers Symposium, theranostic applications are being developed, with a number of clinical trials of PSMA-targeted therapy underway.
Our featured expert, Peter R. Carroll, MD, MPH, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD, and Dr Carroll’s perspectives on these emerging data are presented here.
Peter R. Carroll, MD, MPH
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“There is increasing evidence that PSMA-avid disease can be effectively targeted with radioligand therapy, such as 177Lu-PSMA-617 (LuPSMA), with limited toxicity. This is a promising approach for which we eagerly await additional reporting from ongoing clinical trials.”
PSMA-based imaging, such as 68Ga-PSMA-11 positron emission tomography/computed tomography, is already improving our ability to detect prostate cancer that is high grade and localized, has spread locoregionally, or has reached distant metastatic sites. It was granted US Food and Drug Administration approval in December 2020 specifically for patients with high-risk disease at the time of diagnosis and for those who have recurred (by prostate-specific antigen [PSA]) after initial treatment. PSMA-targeted therapy is a more recent development, as reflected by emerging data presented at the 2021 Genitourinary Cancers Symposium.
There is increasing evidence that PSMA-avid disease can be effectively targeted with radioligand therapy, such as 177Lu-PSMA-617 (LuPSMA), with limited toxicity. This is a promising approach for which we eagerly await additional reporting from ongoing clinical trials. LuPSMA is a radiolabeled small molecule that delivers therapeutic beta radiation to PSMA-expressing tumors. The salivary glands and kidneys appear to be the major potential side effect–producing sites of off-tumor localization of PSMA-targeted radioligand therapy. Xerostomia has been reported; however, renal side effects, if present, are unclear. Abstract 6 reported on the results of the TheraP study, a randomized phase 2 trial comparing LuPSMA vs cabazitaxel in men with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel. At a median follow-up of 18.4 months, progression-free survival was significantly longer in patients assigned LuPSMA compared with those taking cabazitaxel (rates at 1 year: 19% vs 3%, respectively). The authors concluded that, in patients with docetaxel-treated mCRPC, LuPSMA is a promising alternative to cabazitaxel, with significantly improved PSA, progression-free survival, and overall response rates; fewer G3-4 adverse events; similar effects on global health status; and improvements in some patient-reported outcome domains.
The ideal biological space in which to deploy PSMA-targeted therapy is not yet known, and there may be a benefit for patients along the spectrum of disease burden and stage. A variety of trials are ongoing. Although androgen deprivation therapy plus docetaxel is a standard of care for de novo high-volume metastatic hormone-naïve prostate cancer, outcomes remain suboptimal for many patients. It might be that PSMA inhibition, along with androgen deprivation therapy, could further slow the progression of disease, and, in abstract TPS180, investigators reported that they are testing the hypothesis that LuPSMA prior to docetaxel will result in a higher undetectable PSA rate at 12 months compared with docetaxel alone in those with newly diagnosed high-volume metastatic hormone-naïve prostate cancer.
Abstract TPS177 details progress on plans for the ENZA-p study to explore the hypothesis that the concurrent administration of LuPSMA and enzalutamide will be synergistic in mCRPC. The objectives of the ENZA-p study include to determine the activity and safety of LuPSMA and enzalutamide in patients with mCRPC who are at high risk of early progression on enzalutamide alone.
The applications of PSMA-directed therapy might not be limited to metastatic disease. The high-risk localized setting is the focus of abstract TPS264, which examined the dosimetry, safety, and potential benefit of LuPSMA therapy prior to radical prostatectomy in men with high risk, but clinically localized, prostate cancer (LuTectomy study). Further, the investigation of PSMA-directed treatment strategies is not limited to LuPSMA. Both beta particle (iodine-131, lutetium-177) and alpha particle (bismuth-213, actinium-225) radioligands are at various stages of study. Alpha particles have high energies and a shorter path length compared with beta particles. Finally, PSMA-directed therapy is not limited to targeted radioligand approaches. For instance, as reported in abstract TPS174, a phase 1/2 study of REGN5678 with cemiplimab (anti–PD-1) for mCRPC is in progress. REGN5678 is an anti-PSMAxCD28, a costimulatory bispecific antibody.
References
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Alghazo O, Eapen R, Dhiantravan N, et al. Study of the dosimetry, safety, and potential benefit of 177Lu-PSMA-617 radionuclide therapy prior to radical prostatectomy in men with high-risk localized prostate cancer (LuTectomy study) [abstract TPS264]. Abstract presented at: 2021 Genitourinary Cancers Symposium; February 11-13, 2021.
Azad A, Dhiantravan N, Emmett L, et al. UpFrontPSMA: a randomized phase II study of sequential 177Lu-PSMA617 and docetaxel versus docetaxel in metastatic hormone-naïve prostate cancer (mHNPC) [abstract TPS180]. Abstract presented at: 2021 Genitourinary Cancers Symposium; February 11-13, 2021.
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Hofman MS, Emmett L, Sandhu SK, et al. TheraP: a randomized phase III trial of 177Lu-PSMA-617 (LuPSMA) theranostic versus cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel: initial results (ANZUP protocol 1603). J Clin Oncol. 2020;38(15 suppl):5500. doi:10.1200/JCO.2020.38.15_suppl.5500
Hofman MS, Emmett L, Sandhu S, et al; TheraP Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. [177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet. 2021;S0140-6736(21)00237-3. doi:10.1016/S0140-6736(21)00237-3
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Zhang J, Stein MN, Kelly WK, et al. A phase I/II study of REGN5678 (anti-PSMAxCD28, a costimulatory bispecific antibody) with cemiplimab (anti-PD-1) in patients with metastatic castration-resistant prostate cancer [abstract TPS174]. Abstract presented at: 2021 Genitourinary Cancers Symposium; February 11-13, 2021.
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