Michael J. Morris, MD

The combination of atezolizumab (Tecentriq) and radium-223 dichloride (Xofigo) did not demonstrate a clinical benefit in patients with metastatic castration-resistant prostate cancer (mCRPC), according to results a phase 1b study that were presented at the 2020 ASCO Virtual Scientific Program.

In the trial, investigators sought to evaluate the safety and tolerability of atezolizumab plus radium-223 in patients with mCRPC, who also had bone metastasis, visceral metastasis and/or lymphadenopathy, and progressed after androgen receptor (AR) inhibitors.

In the analysis, data was collected from 45 enrolled patients with mCRPC as of October 4, 2019. In the initial cohort phase, a concurrent dosing schedule (CDS) was evaluated, in which atezolizumab and radium-223 dichloride were administered on the same day. Following this, patients with mCRPC were randomized 1:1:1 to CDS or 1 of 2 staggered dosing schedules, the latter of which atezolizumab or radium-223 dichloride was introduced a full cycle before the other agent. Patients received 840 mg of atezolizumab intravenously every 2 weeks and 55 kBq/kg of radium-223 intravenously 6 times, for 4 weeks or until unacceptable toxicity or loss of clinical benefit.

Grade 3/4 adverse events (AEs) related to atezolizumab and radium-223 occurred in 34% and 27% of patients, respectively Two patients (5%) had grade 5 AEs related to atezolizumab. At a median follow-up of 13.9 months, the confirmed objective response rate (ORR) was 6.8%, the median relapse progression-free survival (rPFS) was 3 months, and the median overall survival (OS) was 16.3 months.

“The important take-home message of the trial is that we saw a fair amount of immunotherapy-related adverse effects, some of which were significant,” said lead study author Michael J. Morris, MD. “There were two grade 5 adverse effects that we did feel were related to atezolizumab. These were typical side effects such autoimmune hepatitis, autoimmune myositis, and other autoimmune activity.”

In an interview with OncLive, Morris, medical oncologist, clinical director, Genitourinary Medical Oncology Service, and Prostate Cancer Section Head, Division of Solid Tumor Oncology at Memorial Sloan Kettering Cancer Center, discussed the phase 1b results of atezolizumab plus radium-223 in patients with mCRPC.

OncLive: Could you elaborate on the rationale of this trial? What prior data suggest that this could be a synergistic combination?

Morris: Radium-223 is an FDA-approved radiopharmaceutical agent that was approved on the basis of prolonging survival in men with bone-dominant metastatic prostate cancer. Preclinical data suggest that, within the area of radium deposition in the bone microenvironment, there is an immune response that may account for at least a portion of its mechanism of action in terms of patient clinical benefit. The reason why we looked at the addition of a PD-L1 antibody, such as atezolizumab, was to leverage that immune effect. We wanted to amplify the immune response and not just on a local level; we wanted to confirm more systemic benefits in patients.

Atezolizumab was given at 840 mg every 2 weeks, until either toxicity or lack of clinical benefit and radium-223 dichloride was given at its FDA-approved dose of 55 kBq/kg every 4 weeks for a maximum of 6 doses. The patient population in the trial comprised men with metastatic prostate cancer. One additional requirement is that men had to have measurable disease so that you could at least see a radiographic effect in either node, which ordinarily you could not see if it was strictly a bone-based disease.

There were essentially 3 different treatment arms that we explored. One was concurrent dosing of radium-223, another was staggered dosing with radium-223 preceding atezolizumab, and the third was staggering dosing with atezolizumab first followed by radium-223. The primary end point of the trial was safety and tolerability, because this was a phase 1b study. Also, because it did have 3 arms, there was an examination [on the] anticancer affects. Additionally, there were correlative studies looking at approximately 3 pre- and posttreatment biopsies to explore immune effects.

[Aside from the adverse effects], in terms of a countervailing clinical benefit, we did not see anything that we didn’t expect to see with either radium-223 or atezolizumab independently. Radium-223 doesn't independently significantly decline prostate-specific antigen levels, and we didn't see any improvement on that with the addition of atezolizumab. There were 3 patients who had significant and durable radiographic responses: one lasted 192 days, another for 275 days, and the third for 337 days.

However, this was within a total patient population of 44 patients. We didn't believe that we could identify who those patients were [that responded], which has frequently been a problem in terms of immunotherapy and prostate cancer. We felt that the toxicity to clinical benefit ratio did not warrant pushing [the combination] forward.

This is a field that still needs to be actively explored. I do think though that, with immunotherapy drugs, we need to have some sense of how we’re going to mitigate the safety signal in terms of immunotherapy-related toxicity.

What are your theories to the lack of benefit observed with the combination treatment in this patient population? Do you have any theories?

The delivery of the radiation here is not necessarily in the same place as the delivery of the immune effects. Radium-223 delivers therapy with a relatively narrow depth of penetration to the bony compartment itself. Now, how much of that impacts the surrounding tumor bed is unclear. The bone microenvironment is a complex place, but it could also be that we’re not maximizing the interaction between these 2 therapies by delivering a bone-seeking radiopharmaceutical opposed to the immunotherapy.

That’s why we're looking forward to seeing the results of tumor-directed radiation therapy, where we’re actually delivering both treatment modalities in an overlapping area of the bone microenvironment.

Reference:

Morris MJ, Fong L, Petrylak DP, et al. Safety and clinical activity of atezolizumab + radium-223 dichloride in 2L metastatic castration-resistant prostate cancer: results from a phase Ib clinical trial. J Clin Oncol. 2020;38(suppl 15):5565. doi: 10.1200/JCO.2020.38.15_suppl.5565