conference reporter

2021 Genitourinary Cancers Symposium

Prostate-Specific Membrane Antigen–Targeted Therapies: Expert Insights

by Peter R. Carroll, MD, MPH

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

Ken and Donna Derr – Chevron Distinguished Professor
Taube Family Distinguished Professor in Urology
Department of Urology
UCSF - Helen Diller Comprehensive Cancer Center
University of California, San Francisco
San Francisco, CA

“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.”

Peter R. Carroll, MD, MPH

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

Abou D, Benabdallah N, Jiang W, et al. Prostate cancer theranostics - an overview. Front Oncol. 2020;10:884. doi:10.3389/fonc.2020.00884

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.

Dekempeneer Y, Keyaerts M, Krasniqi A, et al. Targeted alpha therapy using short-lived alpha-particles and the promise of nanobodies as targeting vehicle. Expert Opin Biol Ther. 2016;16(8):1035-1047. doi:10.1080/14712598.2016.1185412

Emmett L, Subramaniam S, Yan Zhang A, et al. ENZA-p: a randomized phase II trial using PSMA as a therapeutic agent and prognostic indicator in men with metastatic castration-resistant prostate cancer treated with enzalutamide (ANZUP 1901) [abstract TPS177]. Abstract presented at: 2021 Genitourinary Cancers Symposium; February 11-13, 2021.

Ferdinandus J, Violet J, Sandhu S, et al. Prognostic biomarkers in men with metastatic castration-resistant prostate cancer receiving [177Lu]-PSMA-617. Eur J Nucl Med Mol Imaging. 2020;47(10):2322-2327. doi:10.1007/s00259-020-04723-z

Heck MM, Tauber R, Schwaiger S, et al. Treatment outcome, toxicity, and predictive factors for radioligand therapy with 177Lu-PSMA-I&T in metastatic castration-resistant prostate cancer. Eur Urol. 2019;75(6):920926. doi:10.1016/j.eururo.2018.11.016

Hofman MS, Emmett L, Sandhu SK, et al. 177Lu-PSMA-617 (LuPSMA) versus cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel: updated results including progression-free survival (PFS) and patient-reported outcomes (PROs) (TheraP ANZUP 1603) [abstract 6]. Abstract presented at: 2021 Genitourinary Cancers Symposium; February 11-13, 2021.

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

Hofman MS, Violet J, Hicks RJ, et al. [177 Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study. Lancet Oncol. 2018;19(6):825-833. doi:10.1016/S1470-2045(18)30198-0

O’Dwyer E, Bodei L, Morris MJ. The role of theranostics in prostate cancer. Semin Radiat Oncol. 2021;31(1):71-82. doi:10.1016/j.semradonc.2020.07.004

O’Keefe DS, Bacich DJ, Huang SS, Heston WDW. A perspective on the evolving story of PSMA biology, PSMA-based imaging, and endoradiotherapeutic strategies. J Nucl Med. 2018;59(7):1007-1013. doi:10.2967/jnumed.117.203877

Rahbar K, Ahmadzadehfar H, Kratochwil C, et al. German multicenter study investigating 177Lu-PSMA-617 radioligand therapy in advanced prostate cancer patients. J Nucl Med. 2017;58(1):85-90. doi:10.2967/jnumed.116.183194 

Trabulsi EJ, Rumble RB, Jadvar H, et al. Optimum imaging strategies for advanced prostate cancer: ASCO guideline. J Clin Oncol. 2020;38(17):1963-1996. doi:10.1200/JCO.19.02757

Violet J, Sandhu S, Iravani A, et al. Long-term follow-up and outcomes of retreatment in an expanded 50-patient single-center phase II prospective trial of 177Lu-PSMA-617 theranostics in metastatic castration-resistant prostate cancer. J Nucl Med. 2020;61(6):857-865. doi:10.2967/jnumed.119.236414

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. 


This information is brought to you by Engage Health Media and is not sponsored, endorsed, or accredited by the American Society of Clinical Oncology, the American Society for Radiation Oncology, or the Society of Urologic Oncology.   

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