PSMA-Targeted Radionuclide Therapy Shows Preliminary Activity in mCRPC

Scott T. Tagawa, MD, MS

The prostate-specific membrane antigen (PSMA)-targeted alpha-emitter ²²⁵actinium (²²⁵Ac) and radiolabeled monoclonal antibody J591 (225Ac-J591) showed encouraging preliminary safety and efficacy in men with pretreated, metastatic castration-resistant prostate cancer (mCRPC), according to findings from a phase I dose-escalation study (NCT03276572).

In the trial, 22 men with mCRPC who had progressed on ≥1 androgen receptor (AR) inhibitor and docetaxel received a single infusion of ²²⁵Ac-J591. Patients were started at a dose level of 13.1 KBq/kg (cohort 1) and escalated to a dose level of 93.3 KBq/kg (cohort 7).

Results showed that 63.6% of patients experienced any prostate-specific antigen (PSA) decline, and 40.9% experienced >50% PSA decline.

“Fifty-five percent of patients in the study had prior lutetium-177 PSMA-617 (LuPSMA), and we still saw a PSA decline in the majority of patients,” said lead study author Scott T. Tagawa, MD, MS.

In terms of safety, 1 of 6 men in cohort 6 (80 KBq/kg) had a dose-limiting toxicity (DLT) of grade 4 anemia and thrombocytopenia. No grade >2 nonhematologic or grade >3 hematologic adverse events (AEs) occurred. The most common low-grade AEs included fatigue (77%), pain (50%), nausea (27%), xerostomia (27%), and AST elevation (18%).

Investigators are currently enrolling patients into an expanded cohort, in which patients will receive the recommended phase II dose of 93.3 KBq/kg.

In an interview with OncLive, Tagawa, Richard A. Stratton Associate Professor in Hematology and Oncology, associate professor of clinical medicine and urology at Weill Cornell Medicine, and associate attending physician, Weill Cornell Medical Center/New York Presbyterian Hospital, discussed the results of the phase I dose-escalation trial, the advantages of using an alpha emitter and a monoclonal antibody, and the possibility of combining the modality with other classes of agents in prostate cancer.

OncLive: Could you provide a rationale for evaluating ²²⁵Ac-J591 in mCRPC?

Tagawa: PSMA is on the cell surface of prostate cancer cells and a couple other areas of the normal body, such as the salivary glands, kidneys, and small intestine. [However, PSMA] is pretty selective [to prostate cancer]. We can target [PSMA] for imaging as well as treatment.

In terms of treatment, 2 randomized studies have been completed. We're just waiting for results. [Both trials] used a small carrier with a beta emitter. The kinetics of a small carrier versus a large carrier are different. What is attached to it and doing the cell kill is usually lutetium 177. Lutetium 177 is a beta emitter that [in addition to being effective, is easily traceable].

Despite that, it's not able to kill all cells. One reason it may not be able to is because it's not as powerful compared with an alpha emitter. [An alpha emitter] has several thousand-fold more energy and cell killing ability, but the energy travels at a much shorter distance. [An alpha emitter] has to get into the cell or right next to the cell [in order to kill it]. However, if an alpha emitter is in the wrong place, it can cause more severe damage.

Small molecules that are rapidly diffused everywhere where there is PSMA generally don't cause too many problems. However, because they're reaching [non-malignant] PSMA cells, it can cause some dry mouth and other issues. These are mild AEs that tend to get better.

We presented patient-reported outcomes (PROs) with one of those therapies, which were favorable overall. The low-grade toxicities didn't translate into a decline in PROs. We know, at least anecdotally, that there can be severe damage to salivary glands and, in the most extreme cases, loss of taste, and loss of teeth.

This trial used the powerful alpha emitter ²²⁵Ac and an antibody, rather than a small molecule, to take it to the PSMA-positive cancer cells and avoid the kidney, bowel, and salivary glands. Even though we've used the antibody with a beta emitter, this is the first time we used an alpha emitter. We did a dose-escalation study where we started slow and then went up. We planned on 7 different dose levels. We predicted, based on dosimetry, with the antibody that we were going to start to see some toxicity at the fifth dose level, but that that was all based on historic information. We ended up proceeding to the seventh dose level without a DLT in the 6 patients at that dose. That’s the planned [recommended] dose level we’ll use in future studies with multiple doses, as well as combinations.

Could you expand on the safety profile of this treatment?

There were no DLTs at the highest dose; however, at the dose below, 1 patient had a DLT of grade 4 anemia and thrombocytopenia. Additionally, 1 patient had grade 3 anemia. There were no other grade 3 hematologic or nonhematologic [toxicities]. The single most common AE was fatigue in the majority [of patients]. The fatigue was generally grade 1 and limited to a couple weeks. Overall, it was a fairly clean AE profile.

Antibodies have the advantage of avoiding these other sites of disease, but they're in the bloodstream for a long time, so they circulate. As they're going through the bone marrow, they may give radiation to the bone marrow. The alpha emitter, in theory, because of the short range, is not going to lead to a lot of myelosuppression—that's what we ended up seeing. Two out of 22 patients had grade ≥3 myelosuppression. More than half of patients [would’ve experienced that] with the same antibody and lutetium.

Where do you see this treatment fitting into the landscape?

It’s great to be a clinician [in prostate cancer] because we have a lot of different choices. I'm pretty sure that PSMA-targeted radionuclide therapy is going to be one of them in the relatively near future, likely first with a small molecule and a beta emitter, 177LuPSMA. We also know that there are tumors that develop resistance that can then respond to an alpha emitter.

We are hopeful that the increased potency of the alpha emitter will overcome resistance, which is great for a single agent. That being said, the future for the beta and alpha emitters as well as the small molecules and the antibodies is really in combination. Specifically, in combination with AR-directed hormonal therapy, which may increase PSMA and may also help increase radiosensitivity.

[We’re also looking into] combinations with immunotherapy. There are not a lot of randomized trials, but it appears that radiation and checkpoint inhibitors pair well together. [PSMA-directed therapy] should probably also work with chemotherapy and PARP inhibitors. We need to be careful and do those studies to figure out the right dose and schedule. Then, a randomized trial has to prove that 2 [of the agents are] better than 1, or that 3 agents are better than 2. It’s exciting that we have the ability to be able to do those studies.

What questions are you hoping to answer with further research?

I’m excited about combinations. There’s also patient and/or tumor selection. What about PSA imaging? We know from a bigger data set, that spans more than a decade, that some patients with negative PSA scans will still have a response [to PSMA-directed therapy]. I wouldn’t want to exclude a patient who has had a lot of different therapies [from receiving this therapy] based on a scan. That being said, when we look at the data in all-comers, where we have negative scans as well as very bright scans, we see that those that have brighter scans appear to have a higher response rate. Therefore, if we have choices for therapy, and 2 are equal, the “hotter” PSMA scan might respond better to that particular type of therapy.

At the 2019 AACR Annual Meeting, as well as the 2019 Genitourinary Cancers Symposium, we presented a subset of these data on around 20 patients who underwent whole-exome sequencing, and around 50 patients who underwent a number of different targeted sequencing platforms. BRCA2 stood out in terms of a better response, progression-free survival, and overall survival with a PSMA-targeted radionuclide therapy. We can predict that because the mechanism of action of radiation is damaging DNA. Therefore, patients with DNA repair defects might respond better.

Is there anything else about the study you want to emphasize?

We're continuing to expand the study. It’s a very exciting time to be involved in this. There are a number of different trials, including randomized trials as well as those that are moving [PSMA-directed therapy] even earlier in the CRPC setting, as well as moving them into the hormone-sensitive setting.

Tagawa ST, Osborne J, Niaz MJ, et al. Dose-escalation results of a phase I study of ²²⁵Ac-J591 for progressive metastatic castration resistant prostate cancer (mCRPC). J Clin Oncol. 2020;38(suppl_6; abstr 114). doi: 10.1200/JCO.2020.38.6_suppl.114.