EP. 5B: PSMA and the Future of Targeted Therapy

Recently published findings from the VISION trial (NCT03511664) revealed that the novel combination of lutetium (Lu)-177 PSMA-617 (LuPSMA) plus standard of care (SOC) prolonged radiographic progression-free survival and overall survival when compared to SOC alone in treating men with prostate-specific membrane antigen (PSMA) positive metastatic castration-resistant prostate cancer (mCRPC).¹ To explore these findings in more detail, see the fourth article in this New Precision Medicine Approaches in Prostate Cancer series, entitled, “How the VISION trial may change prostate cancer therapy.”

As the United States Food and Drug Administration (FDA) examines LuPSMA through priority review, questions remain about this novel agent. How LuPSMA might be used in combination with other treatments, how the availability of PSMA-positron emission tomography (PET) scans in the US will impact the adoption of LuPSMA, and the effect of LuPSMA on men with castrate-sensitive PC are all unknown. However, targeting PSMA holds promise for PC therapy. Moreover, linking radioactive drugs to cancer cells—as LuPSMA does—attracts experts interviewed for this series as an exciting direction for targeted oncology.

In an interview with Targeted Oncology™, Nicholas J. Vogelzang, MD, FASCO, FACP, discusses how the VISION trial informs the future of bothPSMA biomarking and theranostic precision medicine.

TARGETED ONCOLOGY™: How do the findings from the VISION trial inform the future of advanced prostate cancer therapy?

VOGELZANG: The VISION trial was an exciting advance, but it also left us with a hard, cold reality in that it did not move the needle that much. On average, the benefit was only about 4 to 5 months median overall survival advantage, and that tells us that these cancers are resistant to treatment, as we expected.

The cancers that were treated in the VISION trial were generally pretreated with taxanes and with second- and first-line androgen receptor inhibitors, so we were not considering lutetium-177 as a breakthrough drug for castrate-resistant prostate cancer. Yes, patients live longer. Yes, they have improved quality of life, and yes, it was generally well-tolerated except for the dry mouth and some bone marrow suppression. So it's a well-tolerated drug administered to patients, but it does not cure the patients. That being said, we're looking forward to using it, and it will be something that will again extend life for our patients.

What lutetium-177 offers is a new mechanism of action. It gets the cancer no matter where it is in the body, be it bone or lymph nodes. And it builds upon previous generations of radionucleotides such as radium-223, which, although very effective and life-extending, did not hit this off-tissue disease. In other words, radium only hits the bones. Lutetium hits the bones and the lymph nodes. So, through a different mechanism of action than taxanes and the hormone agents, we have another mechanism of action. This is better than Provenge [sipuleucel-T] because Provenge is immunologic.

Lutetium may be a drug that can be given in combination with other agents. It may be something we could give with androgen receptor inhibitors or with Provenge, or with a taxane. But we don't know that yet, and clinical trials will need to be done to administer the drug with other agents. We do know from a trial in Australia that it had a PFS (progression-free survival) advantage over cabazitaxel, but we don't have the data for overall survival.

TARGETED ONCOLOGY™: Should the FDA approve LuPSMA, how might the medical community adopt this agent?

VOGELZANG: The agent will, of course, be expensive. However, a greater barrier is that a PSMA scan that will probably be required. At the moment, getting a PSMA-PET scan is cumbersome.

Right now, for instance, we don't have widespread availability for the PSMA-PET scan here in Las Vegas. I'm sending my patients to UCLA. We hope to have several PSMA scanners available soon. My friend Oliver Sartor in New Orleans has it, and my friend Ralph Hauke, MD, FACP, and others in Nebraska have it, too. LuPSMA is going to filter through the United States, but right now, the availability of scans is limited, and the availability of lutetium is even more limited.

Patients regularly ask me: Where should I go to get lutetium? They have a limited number of options here in the United States. They may find it in Israel or Australia or Germany. People are clamoring for the drug, no question about that. The sooner we get the final FDA approval and the sooner we have PSMA scans available, the sooner we can treat the patients. And those patients will drive a significant amount of demand for the drug and for the scan.

TARGETED ONCOLOGY™: What are the implications of being able to target PSMA theranostically?

VOGELZANG: PSMA scans are predicated on the assumption that all patients make PSMA, or all prostate cancers make PSMA. That's not true. There is a minority—a small minority—of cancers that don't make PSMA.

Just 25 minutes ago, I saw a patient whose PSA was 0.23 and his PSMA scan was negative. It was disappointing. I don't know where the cancer is; he is unsure in what direction to go. Patients like this don't know whether they should do pelvic radiotherapy or begin systemic hormone treatment or what.

So, the PSMA scans do not reveal prostate cancer lesions 100% of the time. For whatever reason, the PSMA scans are not highly reliable at the low levels of PSA. And certainly, there are certain cancers that do not make high levels of PSA or PSMA, and this leads to false negatives on the PSMA scan.

A very nice study at ASCO in 2020 demonstrated that there is also PSMA heterogeneity. This British study from de Bono's group showed that about 10% or 15% of prostate cancer patients were heterogeneous for PSMA production. There were certain metastasis sites that did not make PSMA. Metastatic sites in the liver and in the lymph nodes did not make PSMA. Therefore, LuPSMA would not be expected to target that metastasis.

I explained that today to the patient whose PSA was low. He grasped the issue, but he was sort of shocked at this idea of tumor heterogeneity. It's disconcerting to the patient. He asked: Does this mean that not all cancer cells make PSMA? I said: Yes, and the same thing holds for PSA. There is tumor heterogeneity, and there is selective uptake of LuPSMA.

This is why a very elegant study out of Australia looked at PET and nuclear radioisotope PET using glucose, and radioisotope PET using lutetium. If the lutetium and the PET scans were not concordant, the patient was not allowed in the study. Some of the metastatic disease was not lutetium-positive, although it was potentially PET-positive.

[S]ome…patients are going to be PSMA-negative in certain metastatic sites, and that…heterogeneity is going to only be amplified as the tumor volume gets larger. I don't think that's a big hurdle to overcome, but it is a hurdle. Right now, we're detecting small amounts of cancer using the PSMA scans after PSA relapse, mostly after prostatectomy and usually in a lymph node or a bone. But for large volumes of prostate cancer in lung, liver, bone, and lymph nodes, there's a significant risk of heterogeneity, and that's going to negatively impact use of lutetium-177 and the other radioisotopes.

I think Novartis is right to link their PSMA scanning and their PSMA therapy in a package. I'm very eager to look at POINT Biopharma. They and Convergent Therapeutics are going to move the lutetium earlier into the hormone-sensitive phase where there is probably going to be a little less tumor heterogeneity, and that hormone-sensitive phase should be able to show more effectiveness of lutetium in the hormone-sensitive phase….[W]e're looking forward to having that trial open here as well. So all in all, a very rich field and potentially one that will eliminate tumor cells earlier before they develop resistance to castration.

TARGETED ONCOLOGY™: How might future research address that tumor heterogeneity and improve outcomes?

VOGELZANG: Well, certainly, new basic science is needed. We need to find additional surface antigens that can be targeted and labeled with other radionucleotides.

For example, I also deal with bladder cancer, and finding nectin-4 on bladder cancer surfaces led to the development of enfortumab [vedotin]. It was an antigen found on bladder cancer cells. Yes, there's some cross-reactivity with skin cells. But in general, nectin-4 was a surface antigen that led to a heterodimeric antibody target that brought cancer cells a chemotherapy agent.

Other drugs like LuPSMA—radionucleotide agents that will target the PSMA pathway or other pathways—are coming down the developmental pathway. This is a good and very appropriate area for drug development.

[L]inking…radioactive drugs to target cancer cells—not only in prostate cancer but other cancers—will be a wave of the future. I look forward to working with these drugs in prostate cancer and in other cancers.

Linked therapies are clearly in the focus of companies across the globe. Those companies are looking at how to link old or new antibodies with old chemotherapies. It's principally about finding an antibody against a new surface antigen. Once the antibody is linked to the cell, a whole host of chemical moieties can be used to target the cell. Endocytosis is a very powerful event. Once you get that antibody on the cell surface, the cell is going to endocytose the antibody along with a radionucleotide, a chemical, or another agent.

I believe firmly that this is a future therapeutic option for many cancers: Find the right antibody on the cell surface, then find the right chemical or radionucleotide payload.…[W]e already have many examples of that in leukemia, lymphoma, and now in bladder cancer, and lutetium will be a good example in prostate cancer.

TARGETED ONCOLOGY™: How might these advances and this ongoing research impact the future of targeted oncology?

VOGELZANG: For many years, there were some problems with the linker technology; for many of the chemicals, the linker was destroyed by the toxin. But that seems to have been largely overcome. For breast cancer, for example, all the linker moieties have become much more stable, and the antibodies have become much more diverse.

But now it's clearly a field that's just logarithmically growing. In almost every cancer now, we have antibodies linked to a whole host of toxins. We're giving them routinely and they seem to be highly effective. So I see a very bright future in prostate cancer. Hopefully, it'll be the same way in other cancers.

Reference

1. Sartor O, de Bono J, Chi KN, et al. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385(12):1091-1103. doi:10.1056/NEJMoa2107322