Prostate-specific membrane antigen (PSMA) is a target that we first learned about more than 20 years ago, but, up until recently, most data had been retrospective in nature, particularly regarding PSMA radioligand therapy. I tend to group therapeutic approaches into the following 3 basic categories: drugs (eg, antibody-drug conjugates), immunotherapy (eg, bispecific antibodies or chimeric antigen receptor T-cell therapy), and radionuclide therapy (eg, radioligand therapy or radioimmunotherapy). With radioligand therapy, a small molecule or ligand peptide is being used to bind the radioactive isotope to the target, whereas radioimmunotherapy uses a whole antibody. 

Of the PSMA-targeted radioligand therapies that are in development, lutetium-177 (¹⁷⁷Lu)–PSMA-617 is the furthest along, with the completion and publication of 2 randomized prospective studies. The phase 2 TheraP study compared cabazitaxel with ¹⁷⁷Lu-PSMA-617 in the treatment of men with mCRPC with prior docetaxel exposure. More than 90% of patients had previous androgen receptor pathway inhibitor exposure as well. This was a highly selected patient population, with stricter imaging-based selection than most other studies, and we saw an improvement in prostate-specific antigen response rates with ¹⁷⁷Lu-PSMA-617 compared with cabazitaxel. The phase 3 VISION trial included a late-line population (ie, patients could have had multiple lines of therapy and usually had at least 2-3 prior lines). The addition of ¹⁷⁷Lu-PSMA-617 to best standard-of-care therapy led to an overall improvement in the dual primary end point of radiographic progression-free survival and overall survival. The US Food and Drug Administration (FDA) approval of ¹⁷⁷Lu-PSMA-617 is anticipated soon.*

Two other drugs that are in phase 3 development are ¹⁷⁷Lu-PNT2002 (formerly ¹⁷⁷Lu-PSMA-I&T) and TLX591 (formerly ¹⁷⁷Lu-J591). ¹⁷⁷Lu-PNT2002 incorporates a small-molecule ligand and has been labeled for both imaging and therapy using lutetium. TLX591 (also known as ¹⁷⁷Lu-DOTA-rosopatamab) uses a PSMA-targeted antibody. ¹⁷⁷Lu-PSMA-617, ¹⁷⁷Lu-PNT2002, and TLX591 are being evaluated in phase 3 trials in chemotherapy-naive mCRPC populations. ¹⁷⁷Lu-PSMA-617 is also being studied in metastatic noncastrate (hormone-sensitive) prostate cancer.

All of these therapies will invariably have side effects, and patients in the intervention arm often might have an increase in adverse events compared with patients in the control arm. It is important to look at the exposure-adjusted incidence of side effects, and this was reported in a post hoc analysis of the VISION trial at this year’s Genitourinary Cancers Symposium (abstract 85). Investigators accounted for the longer safety observation period in the ¹⁷⁷Lu-PSMA-617 arm (due to the longer radiographic progression-free survival) and reported a comparable incidence of treatment-emergent adverse events between arms. Despite an increase in adverse events for most FDA-approved drugs, quality of life is usually not worse and is rather often better because the side effects of uncontrolled cancer are worse than the side effects of the treatment. 

With an eye to implementing ¹⁷⁷Lu-PSMA-617 for the treatment of mCRPC, Gajra et al explored the perceptions of community oncologists who were invited to attend a virtual meeting on the VISION trial data (abstract 120). Most people found the trial data on ¹⁷⁷Lu-PSMA-617 in mCRPC to be compelling and indicated that they are likely to incorporate it into the treatment of their patients, if it is approved by the FDA. They also foresaw barriers to its use in their community settings. All of our therapeutic agents have the potential to be toxic to others upon exposure, and there are special precautions that must be taken with each therapy; this remains especially true for radioactive products. For example, the half-life of lutetium is approximately 1 week, so facilities must be equipped to handle all of the logistics of radiotherapy, including storage and safe disposal.

In thinking about an optimal biological space for implementation, the path forward will involve the investigation of existing and more mature agents earlier in the disease course, in the chemotherapy-naive and hormone-sensitive settings. The risk of androgen receptor/PSMA-negative disease, such as small cell neuroendocrine prostate cancer, is greater in a patient who has previously received multiple lines of therapy. Likewise, the risk of mutations associated with radiation resistance, such as TP53 mutations, also increases over several lines of therapy. For these reasons, ¹⁷⁷Lu-PSMA-617 should, in theory, work much better earlier in the disease course, and so, moving forward, that is one avenue of research that is likely to improve the number of patients who can benefit from this therapy and the duration of response. 

Other promising areas include combinations and the incorporation of alpha emitters. There is a rationale for checkpoint inhibition together with radiation and hormonal therapy, and such combinations are already being explored in a randomized fashion.

*Addendum: On March 23, 2022, subsequent to this interview, the FDA approved lutetium Lu 177 vipivotide tetraxetan (formerly referred to as ¹⁷⁷Lu-PSMA-617) for the treatment of progressive PSMA-positive mCRPC. The FDA also approved a complementary gallium-68–based agent indicated for positron emission tomography of PSMA-positive lesions.