Search and Destroy
By Beth W. Orenstein
Vol. 23 No. 6 P. 16
Radionuclides that target and kill advanced prostate cancer cells show great promise.
It is estimated that 34,500 men in the United States die from prostate cancer each year, making it the second leading cause of cancer death among males in America. Some prostate cancers are slow growing, but others are advanced (metastatic). Approximately one-half of men with prostate cancer eventually develop metastatic disease. One type of metastatic disease, metastatic castration-resistant prostate cancer (mCRPC), which is able to grow and spread despite hormone therapy, is particularly lethal. It has a median life expectancy of five years.
There is some good news, however. Treatment of mCRPC has taken major steps forward recently with the development of theranostics, radioactive substances that can be used to visualize and destroy cancer cells while minimizing harm to normal cells. Theranostics also allow physicians to determine how well a treatment is working.
In 2021, the FDA approved several PET and PET/CT diagnostic imaging tests for prostate cancer that rely on the prostate-specific membrane antigen (PSMA) biomarker. PSMA, a protein, is found in overabundance on the surface of cancer cells, especially those that have spread, and is found in more than 80% of men with prostate cancer. It can show physicians exactly where metastatic prostate cancer is progressing and where it may have spread in the body.
PSMA-directed imaging technology has played a key role in the development of these targeted radionuclides. With this imaging technology, pharmaceutical companies have the impetus to develop molecules that seek out and attach to PSMA, enabling them to deliver radiation that damages cancer cells’ DNA and destroys them, says Jim Harvey, PhD, senior vice president and chief science officer of NorthStar Medical Radioisotopes, LLC, in Beloit, Wisconsin. North-Star is poised to be the first large-scale commercial manufacturer for production of therapeutic radioisotopes.
In March 2022, the FDA approved 177Lutetium (Lu)-PSMA-617 (Lu-177 Vipivotide Tetraxetan) as a radioligand therapy for previously treated patients with PSMApositive mCRPC whose cancer is progressing. To be eligible, patients must have previously undergone androgen receptor inhibition and one to two lines of taxane-based chemotherapy.
Developed by the pharmaceutical company Novartis, 177Lu-PSMA-617 is one of several theranostics that are opening a greatly needed avenue of treatment for patients with advanced metastatic prostate cancer and could help patients achieve better survival outcomes, especially when used in combination with the current best standards of care, Harvey says.
“Clearly, we see the therapeutic radioisotopes market as the future for advanced prostate cancer,” he says. “It has the potential to grow to well more than $30 billion by 2030 across all nuclear medicine applications.”
Lu-177 for advanced metastatic prostate cancer has garnered much of the attention of late, Harvey says, “but if you look at the literature, there also has been significant advancement in the use of actinium-225 (Ac-225) and other therapeutic radioisotopes.”
A number of companies are doing research on different radiopharmaceuticals and are in different clinical stages, adds Frank Scholz, PhD, president and chief operating officer at NorthStar. Because early results have been promising, “more and more capital is going into this space,” he says.
Theranostics in Development
Eventually, the executives say, these theranostics, used alone or in combination, will be game changers, allowing men whose prostate cancer has spread despite receiving multiple treatments to not only survive but also live well. “Whether that’s in three, five, or seven years, I can’t predict,” Harvey says. “But I can tell you that, at some point, maybe as soon as 10 years from now, we will look back on things and see there are several approved therapies. I do believe that will happen.”
Another possibility, Harvey says, is to be able to use PSMA-directed therapy as a way to prevent metastatic disease, rather than using it only after the prostate cancer has spread. “While some radionuclides will work out and some might not, they have the potential to reshape prostate cancer treatment. The big picture? It is really, really promising,” he says.
In fact, several therapeutic radionuclides are in development for the treatment of advanced prostate cancer.
Convergent Therapeutics and Ac-225
NorthStar Medical Radioisotopes and Convergent Therapeutics Inc recently announced the signing of a long-term supply agreement for the therapeutic medical radioisotope Ac-225. Convergent, a clinical-stage radiopharmaceutical company, will use NorthStar’s Ac-225 to radiolabel its lead asset, CONV01-α, a PSMA-targeted monoclonal antibody, which it is investigating as a potential treatment for prostate cancer.
Harvey says clinical research and commercial use of Ac-225 have been severely constrained by chronic short supply due to limitations of current production technology. However, he says, NorthStar will use its electron accelerator technology to produce noncarrier-added Ac-225 that is free of long-lived radioactive contaminants and byproducts associated with other production methods that pose regulatory and waste management challenges for manufacturers or health systems.
University of Wisconsin-Madison and NM600
Researchers at the University of Wisconsin-Madison have exploited the ability of cancer cells to selectively sequester and retain phospholipids. The group, led by Jamey Weichert, PhD, and Reinier Hernandez, PhD, designed and patented an alkylphosphocholine chelate analog, called NM600, that is specifically accumulated and retained in prostate cancer. They then radiolabeled it with the alpha-emitter isotope, Ac-225, to perform targeted alpha radiotherapy.
“We compared the therapeutic effects of NM600 radiolabeled with Ac-225 with the effects of NM600 radiolabeled with a beta emitter, Lu-177, and we found that targeted alpha therapy provided much better results [improved antitumor effects and increased overall survival],” says Carolina A. Ferreira, PhD, a research associate on the project. “Interestingly, we demonstrated that beneficial immunological effects were behind the enhanced antitumor effects of alpha radiation. These findings suggest that alpha emitters may be well-suited for combination therapies, including immunotherapy.”
Their work was presented at the SNMMI 2022 Annual Meeting in June.
Ferreira says NM600 has several properties that make it promising for targeted radionuclide therapy (TRT), including the following:
• It accumulates preferentially in the tumor tissue with minimal uptake in off-targeted tissue.
• It gets retained in the tumor tissue over a long period of time (it isn’t rapidly cleared from the tumor tissue).
• It is excreted through the hepatobiliary route and not the kidneys, meaning it usually circulates longer and can accumulate to a greater degree in the tumor.
“Altogether, it can allow for a higher radiation dose to be absorbed by the tumor tissue and cause antitumor effect,” Ferreira says.
Given its targeting mechanism using lipid rafts, which are abundantly present in virtually all cancer types, a unique advantage of NM600 is that it is “broad spectrum. It can target several types of tumors, not only prostate cancer, and it is relatively less affected by tumor heterogeneity, compared to other receptor-based targeting agents,” Ferreira notes.
UCLA and 177Lu-PSMA
Researchers at the University of California in Los Angeles (UCLA) studied men with mCRPC who were treated with 177Lu-PSMA therapy to determine which patients were most likely to benefit from the treatment. They studied 124 men with mCRPC who underwent Lu-PSMA therapy and had PSMA-PET/CT at baseline and PET at 12 weeks. Three blinded readers looked for the appearance of new tumor lesions and changes in PSMA-tumor volume. They developed a novel framework for Response Evaluation Criteria In PSMA-imaging (RECIP) version 1.0. RECIP 1.0 was able to successfully classify responses at 12 weeks into complete or partial response, stable disease, and progressive disease.
The authors concluded that PSMAPET/CT evaluated by RECIP 1.0 was a prognostic tool for overall survival and can be used as an early response biomarker to monitor the efficacy of Lu-177 in men with mCRPC. They published their findings in April in the Journal of Nuclear Medicine. “Our study was done with patients treated with Lu-PSMA 177 therapy, but we do believe that these criteria can be used with other treatments,” says lead author Andrei Gafita, MD.
An earlier study was published in August 2021 by Gafita et al in The Lancet Oncology. Using information from hundreds of men with mCRPC, the researchers at UCLA and five other institutions across Europe, Australia, and the United States also developed a prognostic tool, commonly referred to as a nomogram, designed to estimate the risk of progression-free and overall survival for patients treated with 177Lu-PSMA radioligand therapy. The nomogram can assist physicians when considering treating patients with Lu-PSMA radioligand therapy, Gafita says, but it is not a substitute for clinical judgment and should not dictate clinical decision making.
The 177Lu-PSMA nomogram can calculate individual patient risk based on clinical and imaging characteristics before treatment initiation. A risk calculator, available online at www.uclahealth.org/nuc/nomograms, can automatically predict patient outcomes. After risk calculation, the nomogram automatically generates a report that can be saved in PDF format. The report provides detailed information on the calculated risk, along with an explanation of the input of each parameter on a patient’s predicted outcome, Gafita says.
Their tool and research are important, Gafita says, because “once we can do good selection in those patients, this treatment will work incredibly well. Patients will benefit a lot from this treatment, once we know which ones are the best candidates for it.”
Blue Earth Diagnostics and 18F-rhPSMA-7.3
Biochemically recurrent prostate cancer can be a locally recurrent disease, metastatic disease, or both, says Phillip Kuo, MD, PhD, of the departments of medical imaging, medicine, and biomedical engineering at the University of Arizona in Tucson, and Invicro in Needham, Massachusetts. Kuo and colleagues studied the use of diagnostic PSMA-PET imaging, with the investigational PET radiopharmaceutical 18F-rhPSMA-7.3, in men with biochemical recurrence of metastatic prostate cancer. They also presented findings from Blue Earth Diagnostics’ Phase 3 SPOTLIGHT trial in an oral presentation at the SNMMI 2022 Annual Meeting.
Overall agreement between all three blinded readers who received identical training was assessed and repeated for the regions of the prostate/prostate bed, pelvic lymph nodes, and other (extrapelvic) sites (lymph nodes outside the pelvis, soft tissue/parenchyma, and bones). Results showed that agreement was high across all readers. They found that interreader agreement for 18F-rhPSMA-7.3 PET/CT was more than 75% overall and greatest for the pelvic lymph node region, with more than 87% concordance. Intrareader agreement was more than 85% overall.
“Such high reproducibility, particularly for extraprostatic regions, is clinically valuable, due to the potential of these findings to influence patient management,” Kuo says.
In a press release about the research, David E. Gauden, DPhil, CEO of Blue Earth Diagnostics, a division of Bracco Imaging, says that “in designing the image interpretation training to be used for the 18F-rhPSMA-7.3 Phase 3 program, we drew upon Blue Earth Diagnostics’ expertise and experience in designing PET image interpretation programs and training for commercialized Axumin (fluciclovine F 18). We selected 18F as the isotope of choice for PET imaging with rhPSMA in consideration of its spatial resolution and resulting high quality of PET images, and its physical half-life, which greatly facilitates ease of large-scale manufacturing and distribution for broad-based patient access. 18F-rhPSMA-7.3 represents a new class of high-affinity PSMA-targeted PET radiopharmaceuticals. Early studies of 18F-rhPSMA-7.3 showed a high binding affinity for PSMA, together with biodistribution data suggesting limited urinary activity.”
Are these radiopharmaceuticals expected to be curative, or is longer survival the goal?
“I believe that the ultimate goal is always to develop a cancer treatment that is curative,” Ferreira says. “However, achieving that goal, especially in highly aggressive cancer types such as mCRPC, can be a challenge, so we cherish every improvement in overall survival in those patients. A good novel treatment is one that can improve overall existing statistics and provide insights for further therapeutic improvements.
“We anticipate that, as some radiopharmaceutical therapies move toward the front line, significant improvement in survival will be observed,” she continues. “We also believe that a great opportunity for actual cures lies in combining TRT agents with immunotherapy in order to not only stimulate the immune system to detect and kill cancer cells systemically anywhere in the body but also to induce T cell memory that rejects future tumor cell challenges, creating an in situ vaccine effect.”
A significant advantage of this treatment is its targeted and personalized character which allows for patient selection based on nuclear imaging scans, Ferreira adds. Additionally, she says, these agents can target metastatic disseminated disease, which conventional radiation therapy cannot do. Finally, when compared with other systemic, targeted, or nontargeted therapies, radiopharmaceutical agents are generally well tolerated.
The main disadvantages are the technical and logistical complexities associated with radiopharmaceutical agents, including radiation safety concerns regarding transportation, handling, and waste management, as well as the need for highly qualified personnel and the short shelf-life of the agents, Ferreira says.
Much research still needs to be carried out in order for physicians to understand TRT’s impacts, the differences between TRT agents, and radionuclide choice, as well as the combination of TRT with other therapeutic modalities such as immunotherapy, Ferreira says. “So far, our agents have shown promise in several animal models of prostate cancer; thus, our efforts are now being shifted toward more translational work, including investigational new drug-enabling studies necessary to obtain FDA clearance to start clinical testing.”
Harvey says radioisotope therapy for prostate cancer is making headlines these days, but at many conferences, he hears talk of using TRT for other cancers, such as breast and brain (glioblastomas), as well as use in neuroendocrine tumors. There’s also interest in expanding the use of lutetium in other tumor types, he notes.
Harvey believes prostate cancer TRT research seems to be “laying the groundwork” and is optimistic about what it will someday mean for those with a variety of advanced cancers.
— Beth W. Orenstein, a freelance medical writer in Northampton, Pennsylvania, is a regular contributor to Radiology Today