Tagawa Highlights Promise of Potent PSMA-Targeted Radionuclide Therapy in mCRPC

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Scott T. Tagawa, MD, MS, FACP, provides background on radionuclide therapy, sheds light on the key findings from the trial, and discusses future directions with 225Ac-J591 in mCRPC.

Scott T. Tagawa, MD, MS, Richard A. Stratton Associate Professor in Hematology and Oncology

Scott T. Tagawa, MD, MS, Richard A. Stratton Associate Professor in Hematology and Oncology

Scott T. Tagawa, MD, MS

Prostate-specific membrane antigen (PSMA)-directed radionuclide therapy has garnered interest as a potentially effective and tolerable treatment modality for men with metastatic castration-resistant prostate cancer (mCRPC), said Scott T. Tagawa, MD, MS, FACP, who added that radiolabeled alpha emitters could have clinical utility for patients who have not responded to standard therapies.

A phase I dose-escalation trial (NCT03276572) evaluated the PSMA-directed alpha emitter 225Actinium (225Ac) radiolabeled with the monoclonal antibody J591 for the first time in humans, explained Tagawa. Findings from the study demonstrated that the regimen was tolerable. Only 1 patient experienced a dose-limiting toxicity (DLT) of grade 4 anemia and thrombocytopenia at the highest dose level of 80 KBq/kg.

Early signals of clinical activity were also noted with 225Ac-J591. Moreover, these signals appeared to indicate long-term responses in a heavily pretreated patient population.

"This is a relatively small study, but the results are in line with our hypothesis," said Tagawa, who is the principal investigator of the trial. "We [showed that we can] safely administer a potent PSMA-directed alpha emitter using a monoclonal antibody without DLT.”

In an interview with OncLive, Tagawa, the Richard A. Stratton Associate Professor in Hematology and Oncology and an associate professor of clinical medicine and urology at Weill Cornell Medicine, and associate attending physician at Weill Cornell Medical Center/NewYork-Presbyterian Hospital, provided background on radionuclide therapy, shed light on the key findings from the trial, and discussed future directions with 225Ac-J591 in mCRPC.

OncLive: Could you discuss the preclinical rationale that led to the phase 1 trial?

Tagawa: This is a phase 1 dose-escalation study using 255Ac-J591, which is a PSMA-directed monoclonal antibody radiolabeled with an alpha emitter.

PSMA is a cell surface target expressed on prostate cancer tumor cells, as well as a couple other areas of the body including the kidney, small bowel, and salivary glands. PSMA can be targeted with large molecules such as an antibody, or small molecules such as a ligand. Both target PSMA successfully. However, their circulating times are different; antibodies tend to circulate for a longer time compared with small molecules.

The areas they reach depends on the size [of the molecule]. The antibodies cannot get to areas such as the kidneys, salivary glands, and small intestine because of their size.

Could you shed light on the difference between alpha emitters and beta emitters?

We can label these antibodies or small molecules with drugs, other targets, or radionuclides; this has been done for the longest time.

One of the small molecules radiolabeled with a beta emitter is close to approval [in the United States]. Beta emitters are weaker in terms of the amount of energy per radionuclide, but they have a longer range. They can land many mm or even cm away from a tumor cell. An alpha emitter, on the other hand, is 1000-fold more potent per radionuclide than a beta emitter, but it does not travel far. A neighboring cell may get hit, but cells farther away are not going to be affected.

What was the objective of the study?

We wanted to deliver this potent alpha emitter to cells while avoiding some of the more sensitive PSMA-expressing organs, such as the salivary glands. Therefore, we used the antibody.

The antibody circulates for a long time and can get into the bone marrow. When it is labeled with a beta emitter, there is significant myelosuppression. It is reversible and we know when it is going to happen, so [it can be mitigated] with chemotherapy. Nonetheless, there is myelosuppression [with chemotherapy as well].

We theorized that because of the short range of an alpha emitter, we were not going to see much in the way of myelosuppression.

Could you discuss the development of the antibody from preclinical research to the phase 1 study?

This antibody has been used in humans for more than a decade. However, this is the first time it was radiolabeled with an alpha emitter in intent-to-treat humans.

We started off with preclinical studies. Radiohistory studies showed stability [with the agent]. Then, we went into safety studies with mice, followed by xenograft studies with mice showing tumor shrinkage. We used those studies to develop this first-in-human phase 1 study.

We delivered a single dose of this particular radiolabeled antibody in this trial. The dose was fairly low in terms of what we thought was going to lead to toxicity. Because of the toxicity, we hypothesized that we'd see some efficacy at the lower doses.

Because of our long history with different beta emitters, we were relatively aggressive [with dose-expansion]. We started low but [escalated therapy] in single subjects in each cohort. We would treat 1 subject, wait at least 2 months, and as long as there was no more than grade 1 toxicity, we [increased the dose]. We [escalated therapy] until we reached the fifth dose level, which we predicted [would start to result in] toxicity. We also slowed down if one of those first 4 dose levels had grade 2 or greater toxicity.

What were the inclusion criteria for the trial?

In order to be enrolled, patients had to have progressive mCRPC by standard Prostate Cancer Working Group criteria. Patients were required to have at least 1 of the potent androgen receptor (AR) pathway inhibitors, such as abiraterone acetate (Zytiga) or enzalutamide (Xtandi). The patients had to have had at least 1 course of chemotherapy, refused chemotherapy, or were deemed unfit for chemotherapy.

An unlimited number of prior lines of therapy were allowed except for bone-targeted beta emitters, such as strontium or samarium therapy, which are not used so much anymore. Radium-223 dichloride (Xofigo), as well as PSMA-targeted beta emitters, such as lutetium, were allowed.

Patients received standard CT or MRI scans, plus a bone scan. Additionally, patients had a PSMA PET scan using 68Ga-PSMA-11 PET. That scan was used as a baseline biomarker but was not used to select patients. Regardless of the results of the PET scan, patients could get treated.

We followed patients on weekly, 2-week, and 4-week intervals with regular labs, adverse event (AE) assessment, and standard and PET imaging during follow up.

Patients also had baseline circulating tumor cell (CTC) count by the CELLSEARCH® methodology, followed by another [CTC count performed] at 12 weeks. This served as 1 of the secondary endpoints.

We enrolled 22 men with progressive mCRPC in the trial. The majority had prior chemotherapy and at least 2 lines of prior potent AR inhibitors. For instance, most had at least abiraterone and enzalutamide coming onto the study. The slight majority had prior lutetium PSMA-targeted radionuclide therapy.

What were the results of the study?

All patients who were enrolled on the trial were treated. DLTs were defined as grade 4 hematologic toxicity or grade 3/4 non-hematologic toxicity that would have been potentially treated related.

In terms of primary endpoints, we did not hit a maximum tolerated dose (MTD). In 1 of 6 cohorts, we saw 2 DLTs in 1 patient: grade 4 anemia and thrombocytopenia.

Zero of 6 patients receiving the highest planned dose had a DLT. With this, we declared that there was no MTD and determined that 93.3 KBg/kg of actinium activity is the recommended phase 2 dose.

Although we didn't see DLTs, which meant that the primary end point of the trial was met, some AEs were noted. Beside the single patient who had grade 4 anemia and thrombocytopenia, another patient had grade 3 anemia. All other hematologic and non-hematologic toxicities were grade 1/2.

One issue with PSMA-directed small molecules is that xerostomia can be dose-limiting. In this study, 6 out of 22 patients had grade 1 xerostomia. Of these patients, 5 had previously received lutetium PSMA small molecules. The remaining patient experienced grade 1 xerostomia without having prior exposure [to lutetium PSMA small molecules]. There may be a trend there, although it is unclear because this was not a controlled study.

Additionally, some of our patients who experienced fatigue and nausea also had dry mouth. These [symptoms] did not lead to DLT, because even grade 2 AEs can have an effect on quality of life.

We explored some efficacy markers as secondary end points. We saw posttreatment prostate-specific antigen (PSA) decline in the majority of patients. Despite not selecting for PSMA and the majority having had prior PSMA-directed lutetium, about 40% of patients had a at least a 50% decline in PSA after treatment.

We also saw CTC count control in the majority of patients. The men treated had stable counts, negative counts, or decreased or converted to undetectable counts at 12 weeks.

What are the next steps that are planned for this study?

We are finishing the expansion cohort of this study at the 93.3 KBg/kg dose. Enrollment has slowed down due to COVID-19, but we will hopefully finish enrolling patients in the next few months.

Because of the safety signal, we have several different studies planned for later this year. Again, the exact timing is unclear [given the circumstances], but as this was a single-dose study, [we want to evaluate] multiple doses using regimens, such as lutetium, in which we would look at a fractionated/dose-dense approach as well as the traditional every-6-weeks approach. We also have a couple of studies planned to explore different combinations.

Pending further investigations, how might this therapy impact the paradigm?

There is a lot of potential extrapolations. Jumping ahead, patients could be cured with this regimen if there is not a lot of heterogeneity—meaning all the cells are PSMA-positive—and because of the potency of the alpha emitter. There is a higher probability for cure in combination regimens.

Radioligands in combination with local therapy for biochemical recurrence is a potential future [application] that could lead to cure for patients with very high-risk disease. While it is many years away, the initial [steps have been taken]. Particularly, 177Lu-PSMA is likely to be approved first. However, some patients who tolerate and respond to 177Lu-PSMA will experience disease progression. Due to the potency of an alpha emitter and the fact that PSMA loss is not a mechanism of resistance to this type of therapy, alternative PSMA-directed therapies, such as 225Ac-J591, may be beneficial in the post-177Lu-PSMA space.

In theory, 225Ac-J591 may be better than 177Lu-PSMA. I can envision a head-to-head comparison or a combination study pursuing a monoclonal antibody to deliver the alpha emitter plus a small molecule to deliver the beta emitter. There are advantages and disadvantages to both modalities, but I believe a combination trial would lead to additive, if not synergistic effects.

Is there anything else that you would like the add?

PSMA as a target was identified a couple decades ago. However, at least in the United States, there are no approved diagnostics or therapeutics aside from indium-111 capromab pendetide (ProstaScint), which [is not widely used].

In the short-term, I expect to see approvals for both diagnostics such as PSMA PET, as well as therapeutics. As more patients gain access to PSMA-targeted agents, we are going to be able to identify which patients are likely to benefit in the setting of different therapeutic options.

Tagawa ST, Osborne J, Thomas C, et al. Phase I dose-escalation study of prostate-specific membrane antigen (PSMA)-targeted alpha emitter 225Ac-J591 for progressive metastatic castration resistant prostate cancer (mCRPC). Presented at: the 2020 AACR Virtual Annual Meeting I; April 27-28, 2020. Abstract CT122. bit.ly/35nLbyw.

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