Complete Response to Pembrolizumab in a Patient with Castration-Resistant Prostate Cancer with Both BRCA Positivity and a High Frequency of Microsatellite Instability: A Case Report

There have been few reports of patients for whom a cancer gene panel test for solid tumors revealed the simultaneous presence of BRCA mutation and microsatellite instability (MSI)-high status [1]. We herein report a case in which pembrolizumab treatment achieved a complete response in a patient with bone metastasis of castration-resistant prostate cancer (CRPC) at approximately 18 months after the initiation of abiraterone treatment, and for whom an oncogene panel test demonstrated the simultaneous presence of BRCA2 mutation and an MSI-high status.

The patient was a 71-year-old Asian Japanese man with a history of hypertension. He had no psycho-socioeconomic history nor a family history of hereditary breast or ovarian cancer-related or Lynch syndrome-related cancer. In October 2019, he visited the urology department with the chief complaint of urinary retention and was referred to our department for further examination due to a relatively high prostate-specific antigen (PSA) level of 141 ng/mL. Pelvic MRI revealed an irregularly-shaped neoplastic lesion centered on the prostate gland and extending into the bladder, seminal vesicles, perineum, and anorectal muscles, which showed low signal intensity on T2-weighted imaging and high signal intensity on diffusion-weighted imaging. No significant pelvic lymphadenopathy was observed. A prostate needle biopsy revealed adenocarcinoma with a Gleason score of 5 + 5 = 10 (Fig. 1). Bone scintigraphy and computed tomography (CT) revealed bone metastasis without visceral metastasis (Fig. 2a). Based on the LATITUDE high-risk criteria, abiraterone acetate combined with degarelix was introduced, and intensity-modulated radiation therapy (55 Gy/20 fr) was administered. At 4 months after the initial treatment, the patient’s PSA level decreased to 0.144 ng/mL, and both the primary and metastatic tumors shrank (Fig. 2b). At 18 months after the initial treatment, his PSA level increased to 2.869 ng/mL, and docetaxel (30 mg/m² every 2 weeks) was administered. The liquid CDx Cancer Genome Filing cancer gene panel test showed the presence of a BRCA2 mutation with an MSI-high status (Table 1). After six courses of docetaxel, olaparib was introduced; however, CT showed enlargement of the prostate at 2 months after the initiation of olaparib (600 mg/day) treatment, and his PSA level increased to 15.69 ng/mL. Subsequently, pembrolizumab (200 mg every 3 weeks for 3 cycles, and then 400 mg every 6 weeks for 3 cycles) was administered to the patient. His PSA level decreased, and CT showed that the LNs had decreased in size (Fig. 2c, d, 3, 4). We monitored his laboratory data, including PSA levels, every month and also performed CT every 3 months. His PSA level continued to fall to less than 0.025 ng/mL, and no recurrence was observed at 9 months after the initiation of pembrolizumab treatment. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary file (for all online suppl. material, see https://doi.org/10.1159/000540419).

There have been few reports of prostate cancer with the simultaneous presence of BRCA2 mutations and an MSI-high status. BRCA mutations have been reported in 13% of CRPC patients, and 32 (3.1%) of 1,033 prostate cancer cases are MSI-high/mismatch repair deficient (dMMR) [2, 3]. Sokol et al. [4] reported that 3,446 (1.6%) of 212,417 patients who underwent oncogene panel testing had an MSI-high status. Among these 3,446 patients, 678 (19.7%) had BRCA mutations; this rate, which was 5.3% higher than that in the non-MSI-high group. In prostate cancer patients with BRCA mutations, an MSI-high status was observed in 12.8% of patients with BRCA1 mutations and 3.4% of patients with BRCA2 mutations. Although the overall number of patients with BRCA mutations and an MSI-high status is small, a certain number of patients with BRCA mutations also have an MSI-high status. If olaparib is ineffective after a companion diagnosis of BRCA, a gene panel test might provide an opportunity to detect MSI-high cases.

In the PROfound study, patients with mCRPC with BRCA1, BRCA2, or ATM mutations had significantly longer overall survival with olaparib than with enzalutamide or abiraterone with a hazard ratio of 0.42 after adjusting for crossover cases [5, 6]. In particular, for BRCA mutation cases, the olaparib group showed a significantly longer median OS in comparison to that of the control group (20.1 vs. 14.4 months, HR = 0.63). Based on these results, olaparib was indicated for patients with mCRPC with BRCA mutation-positive mCRPC in Japan. In this case, the patient also had a positive BRCA2 mutation; thus, olaparib was administered, but it was ineffective.

This case showed an MSI-high status based on a liquid biopsy. A previous study showed that immune checkpoint inhibitors are extremely clinically effective in treating patients with MSI-high prostate cancer [3, 7]. In the KEYNOTE-158 trial, pembrolizumab was effective in 34.3% of patients with MSI-high/dMMR non-colorectal solid cancer, including 6 patients with prostate cancer [8]. Abida et al. [3] reported that 6 of 11 mCRPC patients with MSI-high/dMMR who received anti-PD-1/PD-L1 therapy showed a reduction in PSA levels and that 4 showed an imaging response [5]. In our patient, rectal bleeding and bowel movements improved early after the initiation of pembrolizumab, along with his imaging findings.

Sokol et al. [4] reported that olaparib was ineffective and that pembrolizumab was effective in 2 patients with BRCA mutation-positive and MSI-high prostate cancer. They suspected that when a BRCA mutation and MSI-high overlap, the BRCA mutation is monoallelic, meaning that only one of the alleles is expressed (monoallelic) and is less likely to result in a homologous recombination repair defect than a biallelic BRCA mutation, which expresses both alleles.

Monoallelic BRCA mutations are thought to occur due to a high number of oncogene mutations due to an MSI-high status, suggesting that PARP inhibitors would be ineffective and that immune checkpoint inhibitors may be effective. In the present case, the variant allele frequency of the BRCA2 mutation was 0.19%, which is lower than that of MLH1, MSH2, MSH6, and other mutations, as well as the variant allele frequency of CHIP (clonal hematopoiesis of indeterminate potential) and monoallelic mutations. The truncating mutations in MLH1, MSH2, and MSH6 also suggested that the MSI-high/high-TMB status was caused by mismatch repair gene abnormalities, which may explain why olaparib was not effective. The optimal first-line treatment with pembrolizumab or olaparib in patients with both BRCA mutations and MSI-high remains controversial. In addition, PSMA-positron emission tomography is not presently available in Japan. Thus, adequate imaging modalities or biomarkers are needed. The further accumulation of cases and clinical trials is needed to determine the efficacy of this option.

Here, we presented a case of MSI-high bone metastatic CRPC in which the patient showed a complete response to pembrolizumab treatment at approximately 18 months after the initiation of abiraterone treatment.

This retrospective review of patient data did not require ethical approval in accordance with local/national guidelines. Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

The authors declare no conflicts of interest in association with the present study.

All authors received no funding relevant to this study.

T.H., K.Y., N.M., T.K., K.M., and H.U. drafted the manuscript. K.Y., N.M., H.H., Y.K., J.A., S.F., J.O., and M.M. performed the experiments.

Takayuki Hirano and Kosuke Yonezawa contributed equally to this work.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author. This retrospective review of patient data did not require ethical approval in accordance with local/national guidelines.