Multiple FDA approvals are anticipated in the theranostics space.
This could be a big year for FDA approvals of prostate-specific membrane antigen (PSMA)-targeted theranostics aimed at diagnosing and treating advanced prostate cancer.
Theranostics is the combination of therapeutic and diagnostic agents, targeting the same molecular target. PSMA is a leading target for prostate cancer diagnosis and treatment.
PSMA is expressed on the surface of prostate cancer cells.
“Although it is expressed in both benign and malignant prostate tissue, as the cancer becomes more advanced—for example, more castrate resistant—the level of expression of PSMA increases,” said Naomi B. Haas, MD, an associate professor of medicine and director of the Prostate and Kidney Cancer Program at the Hospital of the University of Pennsylvania in Philadelphia.
PSMA is highly overexpressed by the prostate cancer cells, up to 100- or 1000-fold above normal cells. Additionally, up to 95% of prostate cancer cells express PSMA, according to Jeremie Calais, MD, MSc, an assistant professor of nuclear medicine and theranostics and director of the Theranostics Clinical Research Program at the University of California, Los Angeles.
There is level 1 evidence demonstrating that PSMA positron emission tomography/computed tomography (PET/CT) is significantly more accurate than CT and bone scan for staging newly diagnosed high-risk or unfavorable intermediate-risk prostate cancer, according to Declan G. Murphy, MB, BCh, BAO, FRACS, FRCS (Urol), a consultant urologist, the director of genitourinary oncology, and director of robotic surgery at Peter MacCallum Cancer Centre in Melbourne, Australia.
“The proPSMA study1 clearly established the superiority of PSMA PET/CT, and this is therefore rapidly being adopted. Although this technology has been in widespread use in places like Australia and Germany for many years, there has been almost no access in the USA,” Murphy said.
The authors of proPSMA (HREC/16/PMCC/130) investigated Gallium 68 (Ga 68) PSMA-11 PET/CT, which the FDA approved in early December 2020 at the University of California, Los Angeles (UCLA) and University of California San Francisco (UCSF). Ga 68 PSMA-11 is the first PSMA-targeting radioactive agent approved in the US for PET imaging for the detection of cancer cells and localization.
“Gallium 68 has been approved for 2 indications, primary staging before definitive therapy and localization and detection of recurrence based on elevated PSA,” Calais said. “The FDA granted approval only to UCLA and UCSF for now.”
Calais and colleagues also conducted head-to-head research comparing 18F-fluciclovine (Axumin) PET/CT and Ga 68 PSMA-11 PET/CT in patients with early biochemical recurrence after prostatectomy. Results of the study, published in 2019 in The Lancet Oncology, suggest that PSMA had higher detection rates and should be the PET tracer of choice when PET/CT imaging is considered for subsequent treatment decisions in patients with prostate cancer and biochemical recurrence after radical prostatectomy.2
The recent FDA approval ofGa 68 PSMA-11 heralds a new era for prostate cancer imaging in the United States and offers a framework for similar approvals, according to Murphy.
“There are other applications pending for other PSMA tracers including [18F-]DCFPyL, which is a fluorinated tracer that may be more suitable for widespread adoption due to ease of mass production,” Murphy said.
Following on the heels of the approvedGa 68 PSMA-11 PET/CT is a similar agent by Telix Pharmaceuticals called TLX591-CDx, although the company uses a kit to produce it. As a result, the compounding and manufacturing process differs from and is easier than the method approved at UCLA and UCSF, according to Calais. Telix filed its new drug application with the FDA and anticipates a possible approval by the second half of 2021.
Progenics Pharmaceuticals announced in May last year that 18F-DCFPyL (PyL) met the primary end point in the phase 3 CONDOR trial (NCT03739684) in men with biochemical recurrence of prostate cancer. The company’s PSMA-targeted small molecule PET imaging agent, designed to visualize prostate cancer, had a correct localization rate of approximately 85% to 87%. Of the 208 patients in CONDOR, approximately 64% had a change in intended disease management plans due to PyL imaging results, according to a Progenics press release.3
PSMA targeting could have major implications for patients and providers, including urologists who treat patients with advanced prostate cancer. For example, Calais and colleagues are doing studies comparing PSMA PET with conventional imaging scans for staging prostate cancer.
“We are finding that we can detect disease at earlier stages with PSMA PET, which was invisible on imaging before,” he said.
This could make a big difference when patients are thought to have localized disease and have surgery to treat it, when in fact their prostate cancer has metastasized and surgery will fail, according to Calais.
“There is a strong argument now for PSMA PET/CT to replace conventional imaging for the staging of high-risk or unfavorable intermediate-risk prostate cancer,” Murphy said. “This is exactly what we demonstrated in the proPSMA trial, which was a randomized trial comparing conventional imaging with PSMA PET/CT for these [men with new diagnoses]. PSMA PET/CT was 27% more accurate, with significant management impact, less equivocal findings, less radiation dose, and a better health economic assessment.”
Another indication could be for the patient with biochemical recurrence. A rising PSA means there are cancer cells somewhere, but current imaging techniques often cannot detect small areas of cancer, according to Calais. In Australia, the standard approach now is to restage men with biochemical recurrence once the PSA reaches 0.2 ng/mL following surgery, noted Murphy.
“These patients were treated just based on their elevated PSA in the serum, but without any localization of the source of this PSA production,” Calais said. “Now you have PSMA PET that can detect and localize the source of the PSA production.”
Ongoing trials are evaluating PSMA prior to prostate biopsy. The PRIMARY study is comparing the accuracy of PSMA PET/CT with multiparametric MRI (mpMRI) prior to transperineal prostate biopsy; it is fully recruited and results are expected later this year, according to Murphy.4
Changing the physical properties of the radiation can turn a valuable diagnostic tool into treatment. Essentially, radiologists inject the PSMA-targeting agent in the blood and the treatment agent goes where PSMA is expressed. This allows for the local delivery of radiation therapy to those cells, according to Calais.
There is growing anticipation in the US about the potential of PSMA theranostics, including a possible FDA approval in 2021 of PSMA-targeted radiopharmaceutical lutetium-177 PSMA 617 (177Lu-PSMA-617).
The phase 3 VISION trial is investigating 177Lu-PSMA-617 in men with metastatic castrate-resistant prostate cancer who had failed both a novel hormone therapy, such as abiraterone (Zytiga) or enzalutamide (Xtandi), and a taxane-based chemotherapy (NCT03511664). VISION used a diagnostic PSMA PET scan to select patients for the PSMA lutetium 177 therapy, according to investigator A. Oliver Sartor, MD, the C.E. and Bernadine Laborde Professor of Cancer Research and medical director of Tulane Cancer Center at Tulane University School of Medicine in New Orleans, Louisiana.
The international, prospective, open-label, multicenter randomized study has end points of overall survival and radiographic progression-free survival.
“The trial is fully accrued, and there has been a recent disclosure publicly made that the end points have been reached and that currently analysis is under way, with results anticipated in 2021,” Sartor said.
Other prospective trials are under way in Australia to evaluate LuPSMA’s role in earlier stages of prostate cancer, including prior to radical prostatectomy, according to Murphy.
Positive results from VISION would change practice patterns among US physicians, including urologists, who treat patients with advanced prostate cancer.
“Should the PSMA lutetium 177 be approved, then we will feel there is more to offer for our patients. … At the end of the day, the PSMA lutetium 177 has an excellent toxicity profile that makes the adverse events from therapy relatively minimal in most patients. If the trial is positive, the opportunity to offer a therapy of benefit with a relatively small number of [adverse] effects is of course important for both patients and physicians alike,” Sartor said.
Investigators are also using PSMA as a target for bispecific T-cell engager (BiTE) therapy, which is not radioactive. Rather, the technology engages the T cells’ power to overcome the cancer cells’ evasion of the immune system, according to Amgen. The company is among those with a BiTE therapy, AMG 160, in phase 1 trials.
“I can see in the future people also tagging [BiTE therapy] to radioactivity to make the therapy even more effective,” Haas said.
PSMA is also being investigated in trials involving chimeric antigen receptor (CAR) T cells. Poseida Therapeutics is conducting the phase 1 P-PSMA-101-001 trial, which is examining autologous CAR T-cell therapy P-PSMA-101 in patients with metastatic castration-resistant prostate cancer (NCT04249947). Further, Tmunity Therapeutics’ phase 1 trial (NCT04227275) is studying the use of the company’s genetically modified autologous T cells (CART-PSMA-TGFβRDN cells) in patients with metastatic castration-resistant prostate cancer.
Radioligand therapy using 177Lutetium-PSMA remains an investigational option. But with the randomized data that are emerging, Murphy expects the approach could enter clinical guidelines for progressive metastatic castration-resistant prostate cancer following prior therapies within the next year.
PSMA-targeting radionuclide therapy will likely be used mainly for metastatic castration-resistant prostate cancer. For patients with localized disease, however, surgery or external radiation therapy will probably remain standards of care, according to Calais.
Disclosures: Dr Calais receives honoraria from Advanced Accelerator Applications, Blue Earth Diagnostics, Curium Pharma, GE Healthcare, IBA RadioPharma Solutions, Janssen Pharmaceuticals, POINT biopharma, RadioMedix, and Telix Pharmaceuticals, as well as research grants from Progenics/Lantheus. Dr Sartor has stock and ownership interests in GlaxoSmithKline, Lilly, and Noria Pharma Solutions. He has consulting or advisory roles with Advanced Accelerator Applications, Astellas Pharma, AstraZeneca, Bavarian Nordic, Bayer, Bellicum Pharmaceuticals, Bristol Myers Squibb, Celgene, Constellation Pharmaceuticals, Dendreon, EMD Serono, Endocyte, Johnson & Johnson, OncoGenex Pharmaceuticals, Pfizer, Progenics Pharmaceuticals, and Sanofi. He receives research funding from Bayer (Inst); Endocyte (Inst); Innocrin Pharmaceuticals (Inst); Invitae (Inst); Johnson & Johnson (Inst); Merck; and Sanofi (Inst). He gives expert testimony for Sanofi. He receives travel, accommodations, and expenses from AstraZeneca, Bayer, Johnson & Johnson, Progenics, and Sanofi. Dr Murphy reports advisory and speaker activity for Astellas Pharma, Janssen Pharmaceuticals, Ferring Pharmaceuticals, Ipsen, and Bayer.
1. Hofman MS, Lawrentschuk N, Francis RJ, et al; proPSMA Study Group Collaborators. Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study. Lancet. 2020;395(10231):1208-1216. doi:10.1016/S0140-6736(20)30314-7
2. Calais J, Ceci F, Eiber M, et al. 18F-fluciclovine PET-CT and 68Ga-PSMA-11 PET-CT in patients with early biochemical recurrence after prostatectomy: a prospective, single-centre, single-arm, comparative imaging trial. Lancet Oncol. 2019;20(9):1286-1294. doi:10.1016/S1470-2045(19)30415-2
3. Progenics to present results from the phase 3 CONDOR trial of PyL (18F-DCFPyL) in prostate cancer at the American Society of Clinical Oncology 2020 Virtual Scientific Program. News release. GlobeNewswire. May 18, 2020. Accessed February 17, 2021. http://bit.ly/2ZqPHdy
4. Amin A, Blazevski A, Thompson J, et al. Protocol for the PRIMARY clinical trial, a prospective, multicentre, cross-sectional study of the additive diagnostic value of gallium-68 prostate-specific membrane antigen positron-emission tomography/computed tomography to multiparametric magnetic resonance imaging in the diagnostic setting for men being investigated for prostate cancer. BJU Int. 2020;125(4):515-524. doi:10.1111/bju.14999