Metastatic prostate cancer harboring biallelic somatic CDK12 mutation is present in approximately 7% of patients with advanced prostate cancer [1, 2]. These patients have an aggressive clinical course and typically respond poorly to conventional agents. Herein, we report a case with a significant and long‐term response to a platinum‐based combination therapy.
A 64‐year‐old man was diagnosed with poorly differentiated adenocarcinoma of prostate metastatic to abdominal lymph nodes and a normal prostate‐specific antigen (PSA). Tumor tissue showed pathogenic biallelic CDK12 mutations (exon 1: p.Y319fs; exon 1: p.S320fs) and a TMPRSS2‐ERG gene fusion. Tumor mutational burden was low with six nonsynonymous mutations per coding area of the tumor genome. The tumor was negative for programmed death ligand 1 expression by immunohistochemistry, and microsatellite instability was not present. In addition, a mutation of unknown significance in the BRCA gene (exon 10: p.E880K), amplification of the androgen receptor (3+, 100%), and MCL1 were detected. Germline testing (multicancer panel; Invitae Corporation, San Francisco, CA) was negative for pathogenic alterations. After responding to androgen deprivation therapy for only 12 months and having radiographic progression, the patient was treated with carboplatin plus docetaxel (total six cycles with dose of 55 mg/m2 of docetaxel and AUC 5.5 of carboplatin with growth factor support). The taxane plus carboplatin regimen induced a radiographic partial response that lasted 14 months. Upon subsequent progression, the patient had radiation for a local recurrence and was rechallenged with carboplatin plus docetaxel (three cycles). Carboplatin was stopped because of allergic reaction, but his systemic disease was radiographically controlled. At radiographic progression, he was treated with a regimen containing cisplatin (75 mg/m2) and docetaxel (75 mg/m2) for a total of six cycles with another radiographic partial response.
Early data suggest the possibility of immune‐responsiveness to program death ligand inhibition in some patients, possibly because of increased neoantigens [1, 3–5]. Our patient was subsequently treated with pembrolizumab but had no response. Additionally, he had no response to cabazitaxel as a monotherapy, underscoring the potential importance of platinum in the chemotherapy regimen. At this time (more than 3 years after his initial diagnosis with progressive metastatic disease despite androgen deprivation), the patient is clinically doing well and currently undergoing another course using the taxane plus cisplatin regimen.
Three retrospective data sets report the outcomes in CDK12 somatic mutation patients [3, 4, 5], and one of these [3] made reference to platinum use. Reimers et al. [3] retrospectively assessed the outcomes of 46 men with CDK12‐variant prostate cancer. Most men had a Gleason score of 8–10 (88%); 44% presented with metastatic disease at diagnosis. Compared with other genomic subtypes, this cohort exhibited shorter time to metastasis and shorter time to PSA progression on androgen receptor‐targeted therapy. A platinum response was noted but not discussed in three of seven patients, but details regarding the actual regimen were not provided, and durations of response for platinum‐treated patients were not described.
These data underscore the importance of genetic testing in patients with prostate cancer [1, 6] and suggest that further studies of platinum‐based regimens are justified in those with CDK12‐mutant prostate cancer.
Disclosures
Pedro Barata: Clovis, Bayer (C/A), Bristol‐Myers Squibb (RF); Oliver Sartor: Sanofi, Clovis, Bayer (C/A), Merck (RF). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
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