Nivolumab Plus Brachytherapy/ADT Improves Disease Control in Grade Group 5 Prostate Cancer

John Michael "JM" Bryant, MD

The addition of nivolumab (Opdivo) to high-dose rate (HDR) brachytherapy and androgen depravation therapy (ADT) led to a significant reduction in the 2-year risk of distant metastases vs historical control groups in patients with grade group 5 prostate cancer, according to data from the interim analysis of a phase 2 trial (NCT03543189).

Findings presented at the 2023 AACR Annual meeting showed that nivolumab plus HDR brachytherapy and ADT led to an 88% reduction in the 2-year risk of distant metastasis compared with historical control arms treated with standard-of-care therapy alone at Moffitt Cancer Center between January 2013 and November 2021 (HR, 0.12; 95% CI, 0.02-1.00; P = .05).

Additionally, the Rickets immunosuppression genomic signature, which is comprised of 13 genes (CD274, IDO1, FASLG, CTLA-4, PDCD1, LAG-3, HAVCR2, PDCD1LG2, interleukin-10 [IL-10], TNF, Tgfb1, IL-12A, and PTGS2), was strongly correlated to major pathological response to immune checkpoint inhibition (area under the curve = 0.7; P = .01).

“The timing and the method of radiation, specifically the modality of radiation, when combining it with immunotherapy is critically important. We need to take into account the mechanism of action of these agents that we're giving and be a bit more thoughtful in how we combine them,” said lead study author John Michael "JM" Bryant, MD.

In an interview with OncLive^®, Bryant, a radiation oncology resident at Moffitt Cancer Center in Tampa, Florida, expanded on the results of the interim analysis of the single-center, single-arm phase 2 trial for patients with grade group 5 prostate cancer treated with the combination of nivolumab and standard of care, discussed the potential implications of the findings, and highlighted future directions for the study.

OncLive:What was the rationale for investigating nivolumab in combination with HDR brachytherapy and ADT in patients with grade group 5 prostate cancer?

Bryant: Prostate cancer is known to be an immunologically cold tumor, meaning that it does a good job of hiding itself from the immune system. There is evidence stating that radiation in addition to ADT can work to stimulate the immune system. Specifically, by using ablative doses of radiation, we know that we can disrupt the tumor microenvironment, which is one of the main mechanisms that this cancer uses to hide itself. It creates a shell around itself so immune cells can't penetrate [the tumor] and try to irradicate the cancer cells.

[Patients with] grade group 5 [prostate cancer] with a high volume of disease are high- or very high–risk patients. The standard of care is HDR brachytherapy, external beam radiation therapy, and ADT. However, many of these patients still have poor outcomes related to distant metastatic progression while they are still on ADT or shortly thereafter.

If we can time the combination of the immunotherapy right, specifically with HDR brachytherapy, we may be able to disrupt the tumor microenvironment at the right time while the patient is under the influence of ADT. Adding the immunotherapy will allow the immune system to penetrate the tumor microenvironment.

Could you expand on the key findings from the interim analysis of this phase 2 study?

We saw a very strong signal [in regard to] 2-year distant metastasis risk. When we compared 2 historical cohorts of patients who met all the same inclusion and exclusion criteria for this single-center, single-arm study, we saw a reduction of 88% [in the 2-year distant metastasis risk] compared with [historical control arms]. We were happy to see that on interim analysis.

Additionally, there was a strong correlative science component where biopsies were taken, not just at the time of diagnosis, but before each of the 2 fractions of HDR brachytherapy and 1 month after [HDR brachytherapy]. We evaluated the effect of therapy by looking at it under the microscope at these different time points. By using the genomic data that we were able to get from the decipher score when patients were first diagnosed, we were able to identify a number of genomic signatures that predicted early pathologic response.

There were several genomic signatures that were significantly associated with early pathologic response in these patients. Specifically, one that was identified was the Ricketts immunosuppression [signature]. One of the impressive associations with the signature was not only the early pathologic response, but we also saw radiographic responses and more complete responses. It's exciting to see not only a clinically significant reduction in 2-year [risk of distant] metastases on interim analysis, but we were also able to identify this genomic signature that can be used in the future to identify which patients would benefit the most from this addition of immunotherapy with standard of care for patients [with grade group 5 prostate cancer] who tend to [have] worse [outcomes] than [patients with] lower-grade [disease].

Were any of findings from the interim analysis surprising?

One of the more surprising findings was that one of the genomic signatures was associated with immune suppression. There were several immune-related genomic signatures, but [finding] one that was specifically related to higher expression of these genes that create a more immunosuppressive microenvironment and tended to have to better responses to this therapy highlights that local ablative therapy [could] synergize well with immune checkpoint inhibitors. Thinking about the future, there may be other opportunities where we have these tumors that are immunologically cold, [where] with ablative radiation therapy [could synergize well with a checkpoint inhibitor] in order to induce better disease control and a better immune response.

The final analysis for this phase 2 trial is expected in late 2023. What do you hope to gather from these final data?

The final analysis will be the final 2-year follow-up for the last patient enrolled and treated on the trial, so all the data at that point will have matured. We will look at our predetermined end points related to prostate-specific antigen [PSA] control and rate of distant metastases. We are hoping that what we have seen in the interim analysis continues to hold for the distant metastases.

Additionally, PSA [control] was close to significance when we analyzed it with a Cox regression analysis [during the interim analysis]. We are hoping [those data] could become more significant. There is more genomic testing and more radiomic testing that we are doing to try to gain a better understanding of exactly what's happening with different patients who are having different responses, [which could allow us] to identify different end points that we could use as surrogates for outcomes that we are interested in for future studies.

How could this research help inform future studies?

There have been a number of studies that were negative when we tried to combine immunotherapy with radiation. We must be careful that when we're giving the radiation itself or combining it with any other therapies that we're not wiping out the immune cells that we're trying to activate with the other therapy.

One of the clever things about this trial was the timing of immunotherapy, specifically with the brachytherapy portion, giving heed to the radiosensitive lymphocytes, knowing that they're not going to be significantly affected by that form of radiation. Additionally, by having an ablative dose, you're disrupting the cold tumor microenvironment. These are some important thoughts for not just the treatment of prostate cancer, but potentially for other [immunologically cold solid tumors].

We're hoping to be able to use these genomic signatures. The clinical outcomes are great, but one of the exciting things about this trial was the identification of these genomic signatures, specifically for Ricketts immunosuppression, which seems to have a lot of potential to be able to identify patients, either in clinic or in trials in the future, who could benefit from this form of therapy.

Reference

Bryant JM, Sandoval M, Putney R, et al. Combination of nivolumab with standard of care in the management of grade group 5 prostate cancer: interim analysis of a phase II trial. Presented at: 2023 AACR Annual Meeting; April 14-19, 2023; Orlando, FL. Abstract CT157/19.