Immune Correlates May Indicate Responsiveness to Ipilimumab in mCRPC

Sumit Subudhi, MD, PhD

A subset of patients with metastatic castration-resistant prostate cancer (mCRPC) who have low tumor mutational burden (TMB) may benefit from checkpoint inhibition with ipilimumab (Yervoy) if the tumor has a high density of CD8-positive T cells and increased interferon (IFN)-gamma signaling, according to findings from a phase II study published in Science Translational Medicine.¹

At a median follow-up of 45.5 months, the median prostate-specific antigen (PSA) progression-free survival (PFS) was 1.7 months (95% CI, 0.7-8.2) and the median radiographic PFS (rPFS) was 3.0 months (95% CI, 2.5-11.2) in the overall study population. The median overall survival (OS) was 24.3 months (95% CI, 8.5-33.9). Additionally, the best overall radiographic response was stable disease, and the disease control rate was 37%.

“Our results indicate that immune checkpoint blockade can instigate T-cell responses to tumor neoantigens despite a low tumor mutational burden in prostate cancer,” lead study author Sumit Subudhi, MD, PhD, assistant professor of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center, stated in a press release.² “We found specific markers among a subset of patients with the greatest benefit, such as T-cell density and interferon-γ signaling, that may help improve our ability to select patients for treatment with checkpoint blockade.”

To be eligible for enrollment, patients who were ≥18 years old had to have histologically confirmed prostate carcinoma, with radiographic evidence of metastatic disease, adequate organ function, and an ECOG performance status ≤1. Additionally, patients had to have undergone resection of the primary of metastatic site within 3 months of study entry.

The single-center trial enrolled 30 patients with mCRPC between January 2015 and May 2018. Twenty-nine patients received ≥1 dose of ipilimumab at 3 mg/kg every 3 weeks for up to 4 doses.

T-cell responses to cancer neoantigens after treatment with ipilimumab served as the primary endpoint of the trial. Safety, tolerability, and serum prostate-specific antigen level after treatment were also evaluated.

Thirty-eight percent of patients (n = 11) completed the full course of treatment. The median number of doses was 3 (range, 2-4). Patients who had radiographic and/or clinical PFS >6 months (n = 9) also had an OS >12 months and were grouped in the favorable cohort. Patients who had radiographic and/or clinical PFS <6 months (n = 18) either had an OS <12 months (n = 10) or >12 months (n = 8). Patients with PFS <6 months and OS <12 months were grouped in the unfavorable cohort (n = 10).

Patients in the favorable cohort had a median PSA PFS of 19.17 months, a median rPFS of 23.77 months, and a median OS of 44.66 months. Patients in the unfavorable cohort had a median PSA PFS of 0.94 months, a median rPFS of 2.8 months, and a median OS of 4.85 months. At the time of analysis, 67% patients (n = 6) in the favorable cohort were alive versus 0% (n = 10) in the unfavorable cohort.

RNA sequencing of pretreatment samples revealed that the IFN-gamma response pathway signature was higher in patients in the favorable cohort (n = 5) compared with those in the unfavorable cohort (n = 2).

T-cell responses were evaluated in 17 patients, which included 8 patients in the favorable cohort and 4 patients in the unfavorable cohort. Patients in the favorable cohort had higher T-cell gene signatures compared with patients in the unfavorable cohort.

Additionally, T-cell responses to prostate-specific membrane antigen (12.5%; n = 1), prostatic acid phosphatase (37.5%; n = 3), and tumor neoantigens, which were only identified in the favorable cohort, were enhanced after treatment with ipilimumab.

Moreover, the median frequency of nonsynonymous mutations identified with whole-exome sequencing was similar between patients in both cohorts, suggesting that TMB has no bearing on clinical response to ipilimumab.

“We were encouraged to see that prostate cancers with a low mutational burden do in fact express neoantigens that elicit T-cell responses that lead to favorable clinical outcomes,” corresponding author Padmanee Sharma, MD, PhD, professor of genitourinary medical oncology and immunology at The University of Texas MD Anderson Cancer Center, stated in the press release.

In terms of toxicity, 28% patients (n = 8) developed grade 3 treatment-relate adverse events (AEs), the most common of which included dermatitis (10%) and diarrhea (10%). No grade 4/5 AEs were reported.

“Our findings indicate that anti—CTLA-4 immune checkpoint therapy warrants additional studies in order to develop treatment strategies that may improve survival of patients with metastatic prostate cancer,” Sharma concluded.

References

1. Subudhi SK, Vence L, Zhao H, et al. Neoantigen responses, immune correlates, and favorable outcomes after ipilimumab treatment of patients with prostate cancer. Sci Transl Med. 2020;12(537). doi: 1126/scitranslmed.aaz3577
2. Immunotherapy effective in metastatic prostate cancers with specific markers of immune activation [news release]. The University of Texas MD Anderson Cancer Center. Published April 1, 2020. https://bit.ly/34aJC6r. Accessed April 2, 2020.