Pluvicto: A Targeted Radioligand Therapy for Advanced Prostate Cancer

Prostate cancer remains a leading cause of cancer deaths in men. While treatments have improved over the years, advanced metastatic castration-resistant prostate cancer (mCRPC) remains challenging to treat effectively. In March 2022, the FDA approved Pluvicto (lutetium Lu 177 vipivotide tetraxetan), a radioligand therapeutic agent, for a subset of mCRPC patients. This first-in-class approval brings new hope for some patients.

How Does Pluvicto Work?

Pluvicto consists of a targeting molecule linked to a radioactive atom. The targeting molecule selectively binds to prostate specific membrane antigen (PSMA), a protein highly expressed on prostate cancer cells. Once bound, the radiation emitted can kill the prostate cancer cells. The radiation travels a very short distance, allowing focused cell death while mostly sparing nearby healthy tissues.

What Patients Can Receive Pluvicto?

Pluvicto received approval for mCRPC patients who have already been treated with anti-androgen therapies and chemotherapy. Prior to receiving Pluvicto, patients undergo imaging to confirm PSMA-positive disease. If eligible based on test results, age, and adequate organ function, patients receive Pluvicto intravenously, typically once every 6 weeks.

What Are the Benefits?

In clinical trials, Pluvicto modestly increased overall survival by about 4 months compared to standard treatments alone. Patients also saw reduced pain, improved quality of life in some cases, and even elimination of all detectable disease in a small percentage. The convenience of intravenous administration and generally tolerable side effect profile add to its appeal for appropriate patients.

As researchers better understand mCRPC’s complex and heterogeneous nature, matching treatments like Pluvicto to the specific prostate cancer biology should further enhance effectiveness. While questions still remain regarding where Pluvicto fits amongst other newer advanced prostate cancer drugs, it adds another proven option to achieve targeted cell death. Undoubtedly, innovators will continue building upon pioneering agents like Pluvicto, ushering exciting progress in complex prostate cancers.

References

CAS No. 170908-81-3, or DOTA-NHS ester, is an essential part of Radionuclide Drug Conjugate, RDC. It is a chelator seen in the drug Pluvicto, coordinating the radionuclide Lutetium Lu-177*. Note that this product is prone for hydrolysis.

NHS = N-hydroxysuccinimide

The NHS moiety allows bioconjugation of DOTA with a primiary amine to occur so that DOTA, chelated with radionuclides, can be coupled to targeting vectors and delivered to the target site. The reaction schematic is shown below.

* Lu-177 (t1/2 = 6.7 d) is a β− (0.497 MeV), γ (113 keV, 6%) and (208 keV, 10%) emitter, and it is a popular radionuclide for theranostic agent. Lu-177 utilizations not only cover a post-treatment scans, but also allows patient dosimetry to be performed.  

DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), a well-known Bifunctional Chelating Agent (BFCA), is extensively used in radiopharmaceutical research and development. It can form stable complexes with several trivalent metal ions and displays a high affinity for various radionuclides including In-111, Y-86/90, Sc-44/47, Bi-212/213, Ga-68, and Lu-177. These radionuclides stay bound within the DOTA structure at room temperature. However, in the body, the radiometal can detach from the complex, becoming a free ion and reducing the concentration of the radiopharmaceutical complex, as the reverse complexation reaction cannot occur at room temperature. 

Structure of DOTA molecule

DOTA complexes exhibit high thermodynamic stability and are known for their excellent in vivo stability. They are formed with various radionuclides under room temperature conditions until subjected to heat up to 100 °C and within a pH range of 4.0–6.0 over a duration of 5–30 minutes.

References

Due to the fact that the half-lives of radionuclides are short, for example, the half-life of Lu-177 is 6~7 days, the manufacturing and delivery of final RDC prorduct should be completed swiftly. Therefore, we at Unibest suggest global RDC companies and research centers to carefully assess and ensure the stability of RDC supply chains.