Response to pembrolizumab in advanced prostate cancer with predictive biomarkers

Abstract

Introduction

Checkpoint inhibitors targeting PD-1/PD-L1 provide minimal clinical benefit in metastatic prostate cancer (mPC) in an unselected population.^1,2 Pembrolizumab is approved for patients with solid tumors with high microsatellite instability (MSI-H) or high tumor mutation burden (TMB-high); however, data for its activity in prostate cancer harboring these biomarkers are limited, consisting of small case series. Early case series reported that some patients with mPC and MSI-H and/or alteration of a mismatch repair gene leading to MMR deficiency (MMRd) receive clinical benefit when treated with anti-PD-1/PD-L1.^3,4 A more recent case series demonstrated that patients with TMB-H disease have higher PSA response rates and longer progression free survival than patients with TMB-low/median when treated with a checkpoint inhibitor.⁵ In addition to these approved biomarkers, other studies have shown that patients with CDK12 biallelic alteration may also benefit from early initiation of immunotherapy agents, though more recent cases suggest that CDK12 is not a robust biomarker.^6-8 The objective of this study is to better understand which patients with mPC would benefit from treatment with immunotherapy based on their unique tumor biomarkers.

Methods

This single-center study was conducted at Northwestern University. We obtained approval from the institutional review board and a waiver of informed consent. Data were collected from the Northwestern Medicine Enterprise Data Warehouse. We identified all patients with metastatic castration resistant prostate cancer (mCRPC) who were treated with pembrolizumab between May 23, 2017 to December 31, 2023 for a biomarker-driven indication. Data collected included age, stage, and prostate specific antigen (PSA) at diagnosis, prior treatments, metastatic sites, results of molecular testing, and PSA on treatment. PSA response was defined as decline of 50% or greater from baseline prior to therapy. Whether a patient had MSI-High, TMB-High, MMRd, or CDK12 alteration was determined by molecular studies performed as part of routine care. Total time on pembrolizumab was collected by chart review.

Results

Eighteen consecutive patients who received pembrolizumab for biomarker-selected prostate cancer were included in the series (Table 1). The median age at diagnosis was 68 years (range 58–84). Thirteen patients were diagnosed with de novo metastatic prostate cancer (72.2%). Median time on pembrolizumab was 6 months (range 1–47 months).

The best percent change in PSA in response to pembrolizumab is shown in Figure 1A. Seven of 18 patients (38.9%) had a decline in PSA of at least 50%, and all of them had tumors with MSI-H. Of 10 patients with MSI-H and TMB-H, 5 had a PSA response of 50% or greater. Only 2 patients had TMB-H without MSI-H, and neither had a PSA response. Two patients had alterations in CDK12 with neither MSI-H nor TMB-H, and neither of these patients had a PSA response.

Figure 1.

Response to pembrolizumab. (A) Waterfall plot showing best PSA response to pembrolizumab (upper panel). TMB (mutations/megabase) (middle panel). Biomarkers for response to immunotherapy (lower panel). #, PSA progression cut off at 200%. (B) Swimmer plot indicating time on therapy in months. *, treatment is ongoing. MSI-H = Microsatellite instability—high. TMB-H = Tumor mutational burden—high. CDK12 = Alteration in CDK12. For TMB-H, gray indications tumor mutational burden is not available.

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Time on therapy ranged from 1 to 47 months, with 5 patients still on therapy, 4 of them having been on therapy 12 months or longer (Figure 1B). Of the 10 patients on therapy for at least 6 months, all of them had PCa that was MSI-H.

Nine patients had an alteration in a homologous recombination repair (HRR) gene, 5 of them in BRCA2. The median time on therapy for these patients was 8.1 and 11.2 months, respectively.

Discussion

In this retrospective study, we sought to better identify which biomarker-selected patients are most likely to benefit from pembrolizumab and better estimate their likelihood of response. Patients in this study were previously diagnosed with mCRPC. They had previously been treated with hormone therapy in the form of androgen deprivation and/or androgen receptor inhibitors. Many also underwent radiation prior to immunotherapy. All patients with PSA response and all patients on therapy for 6 months or more had MSI-H. TMB-H is often co-occurring with MSI-H. Patients positive for both markers were most likely to have PSA response (60%), similar to a prior series with patients with MSI-H.³ Contrary to other reports, we did not see a correlation between response and TMB.⁵ This was likely because most patients with high TMB also had MSI-H, though the patients with elevated TMB without MSI-H did not have any decrease in PSA. Patients with both biomarkers had the longest time on therapy (median 11.5 months).

There has been interest in synergy between PARP inhibition and immunotherapy for patients with HRR alterations.^9,10 In our cohort, patients with BRCA2 alterations had durable responses to pembrolizumab (median 12 months; Table 1). They also all had MSI-H. It seems likely that the MSI-H phenotype is driving the response. It is less clear what contribution the BRCA2 alteration has, or if in these cases they are passenger alterations.

Durable responses were also seen with ATM, FANCL, RAD54L, and PALB2 mutations. All but one of the patients with one or more of these mutations also had both MSI-H and TMB-H status. The one patient that solely was TMB-H had a PALB2 mutation and had a 207% increase in PSA. The remainder of these patients showed a decrease in PSA from baseline. Again, these mutations are more likely to be passenger mutations rather than pathogenic drive mutations.

These data continue to support biomarker testing for all patients with mCRPC, and use of immunotherapy for biomarker-selected patients, particularly those with both MSI-H and TMB-H.

Author contributions

Nicole J. Altomare (Data curation, Formal Analysis, Visualization, Writing—original draft, Writing—review & editing), Yutai Li (Data curation, Formal Analysis, Writing—review & editing), Clayton Neill (Data curation, Formal Analysis, Writing—review & editing), Maha Hussain (Resources, Supervision, Writing—review & editing), and David J. Vander Weele (Conceptualization, Data curation, Formal Analysis, Resources, Supervision, Visualization, Writing—original draft, Writing—review & editing)

Funding

No funding was used for this study.

Conflict of Interest

D.V.W.: Advisory board, travel, educational talks: Exelixis, Janssen, Bayer, Astellas, Myovant.

Institutional Research Support: AstraZeneca, Pfizer, Genentech, Bayer, Nikang Therapeutics.

MH: 2023-2024

Institutional Research Support:-APCCC (Astra Zeneca), Bayer,Arvinas.

Advisory Boards: Bayer, Tango, Novartis, Convergent, AstraZenea (AZ).

Honorarium for Educational lectures/Educational Cancer Conf:

1. AstraZeneca:

-South Africa Oncology Society lecture.

-2nd International GU Cancer Conference -Prostate Cancer Education program.

-Prostate Cancer Diagnostic Medical Education.

2. Bayer (including travel/accommodation) for 2023 APEX meeting.

3. MJH, MedScape, RTP.

Data Availability

The data that support the findings of this study are available from the corresponding author [D.J.V.] upon reasonable request.

References