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

In an update to his original article, “PSMA Theranostics Is Poised to Change Prostate Cancer Landscape,”

 Ashok Muthukrishnan, MD, MS, addresses the recent FDA approval of lutetium (177Lu) vipivotide tetraxetan (Pluvicto)

 and looks to the potential of radioimmunotheranostics on the horizon.

Prostate cancer theranostics is at an exciting crossroads, with recent FDA approvals of prostate-specific membrane antigen (PSMA)-based cancer molecular imaging and therapy agents.

Ga-PSMA-11 imaging tracer drugs (Illuccix and Locametz) provide 3 options. Although there was some initial confusion on the specific indications for these agents, National Comprehensive Cancer Network and Society of Nuclear Medicine and Molecular Imaging guidelines had recommended the use of all these PET imaging agents interchangeably for initial staging of high-risk prostate cancer, biochemical recurrence, and for patient selection before PSMA-directed therapy.

Recent enthusiasm within the oncology community and patients with prostate cancer stems from lutetium (

Lu) vipivotide tetraxetan (Pluvicto), which received FDA approval in March 2022. The decision to approve 

Lu vipivotide tetraxetan was supported by findings from the international, randomized, phase 3 VISION study (NCT03511664).

Lu vipivotide tetraxetan combined with standard of care (SOC) therapy demonstrated significant improvement in overall survival as well as radiographic progression-free survival compared with SOC alone in patients with PSMA-positive metastatic castration-resistant prostate cancer.

The fanfare and excitement came to a temporary halt with the announcement from Novartis, the manufacturer, about a voluntary temporary suspension of drug production because of potential quality issues in their manufacturing process.

 This issue has recently been resolved by the manufacturer and the drug should be available at the time of this publication.

Just like Lutathera, Pluvicto uses 177Lu that emits beta radiation, effectively delivering “precision” radiation targeted at the PSMA receptors, which is highly expressed in prostate cancer cell lines compared with other normal cells.

Additionally, its degree of expression has been identified as an independent marker for risk stratification in predicting disease recurrence following curative therapy.

Lu radioligand therapy have shown that the drug is highly effective when added to SOC,

 with a meta-analysis showing that around 75% of patients had a reduction of PSA levels, and a further 46% had PSA levels drop by more than half.

Within the next few years, it would not be surprising to see α-based PSMA agents dominate if not entirely replace 

Lu-based agents and play an integral role in prostate cancer therapy practice. Taking it a notch higher, radioimmunotheranostics might usher in the next line of therapy tools for prostate cancer and beyond. One such great example is the antibody-to-prostate stem cell antigen that could be the next potential agent for prostate cancer diagnosis and therapy.

1. Muthukrishnan A. PSMA theranostics is poised to change prostate cancer landscape. 

.May 22, 2021.Accessed June 27, 2022. targetedonc.com/link/1830

2. FDA approves Pluvicto for metastatic castration-resistant prostate cancer. FDA. March 23, 2022. Accessed June 27, 2022. https://bit.ly/3Og8hwx

3. Grauer LS, Lawler KD, Marignac JL, Kumar A, Goel AS, Wolfert RL. Identification, purification, and subcellular localization of prostate-specific membrane antigen PSM’protein in the LNCaP prostatic carcinoma cell line. 

4. Novartis provides update on production of radioligand therapy medicines. News release. Novartis. May 5, 2022. Accessed June 24, 2022. https://bit.ly/3tZV6rP

5. Hupe MC, Philippi C, Roth D, et al. Expression of prostate-specific membrane antigen (PSMA) on biopsies is an independent risk stratifier of prostate cancer patients at time of initial diagnosis. 

. 2018;8:623. doi:10.3389/fonc.2018.00623

6. Sartor O, de Bono J, Chi KN, et al; VISION Investigators. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. 

. 2021;385(12):1091-1103. doi:10.1056/NEJMoa2107322

7. Yadav MP, Ballal S, Sahoo RK, Dwivedi SN, Bal C. Radioligand therapy with 177Lu-PSMA for metastatic castration-resistant prostate cancer: a systematic review and meta-analysis. 

. 2019;213(2):275-285. doi:10.2214/AJR.18.20845

8. Arndt C, Bergmann R, Striese F, et al. Development and functional characterization of a versatile radio-/immunotheranostic tool for prostate cancer management. 

 (Basel). 2022;14(8):1996. doi:10.3390/cancers14081996

Articles

Ashok Muthukrishnan, MD, MS, addresses the recent FDA approval of lutetium 177Lu vipivotide tetraxetan and looks to the potential of radioimmunotheranostics on the horizon.

Pluvicto Approval Launches Theranostics in Prostate Cancer

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.

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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. 

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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.

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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

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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

Pluvicto Approval Launches Theranostics in Prostate Cancer

PSMA Theranostics Is Poised to Change Prostate Cancer Landscape