Ashok Muthukrishnan, MD, MS, is the chief of Nuclear Medicine, and director of Theranostics in the Department of Radiology at the University of Pittsburgh Medical Center in Pittsburgh, PA.

Ashok Muthukrishnan, MD, MS

With the recent success of lutetium Lu 177 dotatate (Lutathera) therapy for neuroendocrine tumor, the field of theranostics has come under a vivid spotlight in the last couple of years from oncologists, nuclear radiologists, cancer researchers, and the pharmaceutical industry. Although research focused on prostate-specific membrane antigen (PSMA) has been ongoing for almost 2 decades, the timing for the emergence of PSMA theranostics could not have been any better. 

Ironically, the term PSMA is not specific to prostate cancer.

It is in fact expressed in hepatocellular cancer and glioblastoma and some renal and colon cancers. PSMA is expressed up to 1000 times in prostate cancer, and its degree of expression seems to correlate with tumor dedifferentiation and the presence of metastases. The fact that current conventional imaging is woefully inadequate in detecting low-volume oligometastatic disease burden in prostate cancer makes PSMA targeting valuable from a diagnostic standpoint.

Limited success has been achieved by the application of anti-PSMA antibody imaging in the past. For example, indium-111 capromab-pendetide (Prostascint) targeted the intracellular epitope of PSMA, but often with poor tumor penetrability.

 Another anti-PSMA agent, 89Zr-Df-IAB2M, a minibody-based PET imaging agent, has better imaging characteristics than indium-111 capromab-pendetide, but its drawbacks include higher radiation exposure due to the relatively long half-life of zirconium-89, increased uptake in sites of inflammation, longer wait times between tracer injection, and the actual imaging.4 Small-molecule PSMA inhibitors, such as technetium (Tc)-99m MIP-1404, have also jumped into the fray, but their disadvantages include resolution limitation involving both Tc-99m and gamma camera imaging.

Ever since gallium (Ga)-68 PSMA-11 was developed and used in clinical evaluation, the utility in prostate cancer management has become clear.

 An abundance of data reinforces its superiority in sensitivity and detection capabilities over those of conventional imaging; in addition, it has high sensitivity and positive predictive value in biochemical recurrence of prostate cancer, even when a patient’s prostate-specific antigen (PSA) levels are very low.

 Also, in comparison with the FDA-approved PET agent, (F)-18 fluciclovine, Ga-68 PSMA PET has demonstrated its superiority in treating disease in the prostate bed and pelvic and extrapelvic nodal regions, as well as in detecting osseous and visceral metastases. The newer F-18–based PSMA tracers—F-18 DCFPyl, for example—have a slight edge over their Ga-68 counterpart, mainly because of enhanced imaging characteristics that help with the detection of nodal micrometastases.

 Also, the relative ease of cyclotron-based production of F-18 can result in bulk manufacturing of the tracer, which increases the possibility of long-distance delivery options and a wider reach than Ga-68 PSMA. Ga-68 PSMA requires a Germanium-68/Gallium-68 generator closer to the point of delivery/site of imaging. Furthermore, only 3 or 4 doses can currently be manufactured in a day, given the innate limitations of such generators.

A caveat of PSMA imaging is that it is nonspecific. The isotope can be taken up in benign entities, such as pneumonia, sarcoidosis, and Paget disease, as well as in other malignant conditions such as liver cancer, transitional cell carcinoma, renal cell carcinoma, and colorectal carcinomas. Although this issue results in false positives, one could say that PSMA imaging’s range of applications and imaging interpretation will only improve over time. In addition, its imaging and therapeutic applications will also eventually be extended to those non-prostate cancers with histopathological proof of high PSMA expression.

Although most of the current literature related to PSMA imaging lies in the space of biochemical recurrence of prostate cancer, there is good evidence that PSMA imaging in initial intermediate- to high-risk prostate cancer helps preoperatively stage the disease better, specifically from a nodal metastases perspective. In a recent study, PSMA PET-CT was instrumental in upstaging initial high-risk prostate cancer to N1 or M1 disease in 22% of men.

Several agents have been developed for therapeutically targeting the PSMA. One such early agent was 90 Yttrium-CYT-356 monoclonal antibody (mAb), which targets the intracellular domain of PSMA, although its outcomes were not very successful.

 Another mAb-based therapy agent, Lu177 PSMA-J591 had slightly better success in a phase 2 trial. However, nearly half of the treated patients had grade 4 hepatotoxicity, likely secondary to the large molecular size of the antibodies, leading to poor penetration in tumors and slow clearance from the circulation.

Then came 177Lu PSMA-617, which, in early trial data from Europe, had shown a favorable clinical outcome: a decline in PSA in 70% of patients. Additionally, a majority of treated patients showed only minor grade 1/2 hematotoxicity, until 2 months after the last dose of the therapy.

Similar promising results have emerged from subsequent clinical trials. In the United States, data were released in March 2021 from the phase 3 VISION trial (NCT03511664), which evaluated the efficacy and safety of 177Lu PSMA-617 in addition to standard of care in 831 patients with castrationresistant prostate cancer who were previously exposed to at least 1 chemotherapy and 1 novel hormonal agent.

 The study met both primary end points—overall survival and radiographic progression-free survival—with a safety profile consistent with data reported in previous trials.

Other trials with encouraging results include those examining PSMA labeled with alpha-emitting radioisotopes such as actinium (Ac)-225. Ac-225 was administered to patients resistant to Lu-177 PSMA therapy, and it had even more promising results than Lu-177.

 In one study of 17 patients with advanced metastatic prostate cancer who were treated with Ac-225 PSMA-617, 82% experienced a PSA decline of ≥90%, and 41% had undetectable PSA levels 1 year after undergoing treatment.

Future studies will help us understand the utility of PSMA theranostics combined with current standard-of-care drugs such as abiraterone acetate (Zytiga) and enzalutamide (Xtandi). The practice of PSMA theranostics is a relatively new concept that, while exciting, portends many organizational and technical challenges for cancer centers across the nation. First and foremost is the need for well-trained interdisciplinary teams who have working knowledge of PSMA imaging and therapy practice guidelines. Not enough medical staff currently in oncologic practice completely understand the concepts of theranostics and radiation safety. In addition, these new theranostic therapies are typically very expensive, due to high manufacturing costs that incorporate the requirements of a highly skilled workforce and of infrastructure that meets high medical practice standards. Also, the use and administration of radioactive substances in patients is subject to stringent rules set by the Nuclear Regulatory Commission.

Despite these challenges, PSMA theranostics will undoubtedly change the prostate cancer landscape in the near future. The preliminary efficacy and safety data on PSMA theranostics hold great promise, and it might be prudent for cancer centers to at least begin discussions on preparing their infrastructure, educating their medical staff, and laying some groundwork for radioactivity-ready short-stay suites as they get ready to welcome PSMA into their practice. The next steps would be to incorporate alpha isotopes onto PSMA, explore possibilities with immunotherapeutic ligands, and investigate other combination treatment methodologies.

1. Wright GL Jr, Haley C, Beckett ML, Schellhammer PF. Expression of prostate-specific membrane antigen in normal, benign, and malignant prostate tissues. 

l. 1995;1(1):18-28. doi:10.1016/1078-1439(95)00002-y 

2. Haberkorn U, Eder M, Kopka K, Babich JW, Eisenhut M. New strategies in prostate cancer: prostate-specific membrane antigen (PSMA) ligands for diagnosis and therapy. 

. 2016;22(1):9-15. doi:10.1158/1078-0432.CCR-15-0820 

3. Wilkinson S, Chodak G. The role of 111indium-capromab pendetide imaging for assessing biochemical failure after radical prostatectomy. 

. 2004;172(1):133-136. doi:10.1097/01.ju.0000132138.02846.08 

4. Holland JP, Divilov V, Bander NH, Smith-Jones PM, Larson SM, Lewis JS. 89Zr-DFO-J591 for immunoPET of prostate-specific membrane antigen expression in vivo. 

. 2010;51(8):1293-1300. doi:10.2967/ jnumed.110.076174 

5. Goffin K, Joniau S, Tenke P, et al. A phase 2 study of 99mTc-trofolastat (MIP-1404) to identify prostate cancer (PCa) in high-risk patients (pts) undergoing radical prostatectomy (RP) and extended pelvic lymph node (ePLN) dissection: an interim analysis. 

6. Afshar-Oromieh A, Haberkorn U, Eder M, Eisenhut M, Zechmann CM. [68Ga]Gallium-labelled PSMA ligand as superior PET tracer for the diagnosis of prostate cancer: comparison with 18F-FECH. 

. 2012;39(6):1085-1086. doi:10.1007/s00259-012-2069-0 

7. Fendler WP, Calais J, Eiber M, et al. Assessment of 68Ga-PSMA-11 PET accuracy in localizing recurrent prostate cancer: a prospective single-arm clinical trial. 

. 2019;5(6):856-863. doi:10.1001/jamaoncol.2019.0096

8. Wondergem M, Jansen BHE, van der Zant FM, et al. Early lesion detection with 18F-DCFPyL PET/CT in 248 patients with biochemically recurrent prostate cancer. Eur J Nucl Med Mol Imaging. 2019;46(9):1911-1918. doi:10.1007/s00259-019-04385-6 

9. Pouliot F, Carroll P, Probst S, et al. A prospective phase II/III multicenter study of PSMA-targeted 18F-DCFPyL PET/CT imaging in patients with prostate cancer (OSPREY): a sub-analysis of regional and distant metastases detection rates at initial staging by 18F-DCFPyL PET/CT. 

; 2020;38(6 Suppl):abstr 9. doi:10.1200/JCO.2020.38.6_suppl.9 

10. Deb N, Goris M, Trisler K, et al. Treatment of hormone-refractory prostate cancer with 90Y-CYT-356 monoclonal antibody.

11. Tagawa ST, Milowsky MI, Morris M, et al. Phase II study of Lutetium-177-labeled anti–prostate-specific membrane antigen monoclonal antibody J591 for metastatic castration-resistant prostate cancer. 

. 2013;19(18):5182-5191. doi:10.1158/1078-0432.CCR-13-0231 

12. Novartis announces positive result of phase III study with radioligand therapy 177Lu-PSMA-617 in patients with advanced prostate cancer. News release. Novartis; March 23, 2021. Accessed April 15, 2021. https://bit. ly/32hhBtN

13. Kratochwil C, Bruchertseifer F, Giesel FL, et al. 225Ac-PSMA-617 for PSMA-targeted α-radiation therapy of metastatic castration-resistant prostate cancer. 

. 2016;57(12):1941-1944. doi:10.2967/ jnumed.116.178673 

14. Sathekge M, Bruchertseifer F, Knoesen O, et al. 225Ac-PSMA-617 in chemotherapy-naive patients with advanced prostate cancer: a pilot study. 

. 2019;46(1):129-138. doi:10.1007/s00259- 018-4167-0

Articles

Although research focused on prostate-specific membrane antigen has been ongoing for almost 2 decades, the timing for the emergence of prostate-specific membrane antigen theranostics could not have been any better. 

Ashok Muthukrishnan, MD, MS | Authors

Articles

PSMA Theranostics Is Poised to Change Prostate Cancer Landscape