Despite being recommended in prostate cancer guidelines, homologous recombinant repair (HRR) mutation analysis is widely underused in patients with prostate cancer, according to real-world data presented at the 2024 ASCO Genitourinary Cancers Symposium (Abstract 210). A major implication of these findings is that many patients with prostate cancer may not receive guideline-recommended treatment (particularly, with a PARP inhibitor) for HRR-mutated metastatic castration-resistant prostate cancer.
In a real-world study, germline or somatic HRR mutation testing was not performed in 40.8% of patients with metastatic castration-resistant prostate cancer. Moreover, just one-third of patients (33.2%) with HRR-mutated disease received treatment with a PARP inhibitor in this analysis.
“The PROfound trial led to the approval of [the PARP inhibitor] olaparib, and in that trial, we saw 20% to 25% of patients [with metastatic castration-resistant prostate cancer] globally harbored HRR gene mutations…. Germline and somatic testing is now recommended by professional guidelines as a standard of care for metastatic advanced prostate cancer patients, both sensitive and resistant, but certainly germline and somatic [testing] is recommended for all patients with metastatic castration-resistant prostate cancer to detect HRR gene mutations and consider options for PARP inhibitors,” stated lead author of the study Neal D. Shore, MD, FACS, a urologist at Atlantic Urology Clinics. “Additional education on tumor testing and PARP inhibitor therapy is warranted, particularly in community oncology and urology settings,” he noted.
Neal D. Shore, MD, FACS
Key Analysis Findings
The current analysis included data on 996 newly diagnosed and actively treated patients with metastatic castration-resistant prostate cancer drawn from a database called IntegraConnect Precision Q, which collated data from 500 practice sites in the United States. Among the patients, 93% were seen in community oncology practice, 6% were seen by community urologists, and 1% were seen by academic oncologists.
The study relied on patient data collected from January 1, 2020, through December 31, 2021. The first PARP inhibitor to be approved for prostate cancer was olaparib (in May 2020); there was an increase in the percentage of patients tested for HRR mutations noted after that approval. HRR mutation testing was conducted in 15% of patients between January 1, 2020, and May 31, 2020. Testing rates then increased to 23% between June 1, 2020, and September 30, 2020, and then they increased again to 62% between October 1, 2020, and December 31, 2021.
In the present analysis, a total of 59.2% of patients (n = 590) underwent HRR mutation testing; 19.8% (n = 117) had germline testing, 59.8% (n = 353) had somatic testing, 4.1% (n = 24) had germline and somatic testing, and 16.3% (n = 96) had unknown testing. The majority of patients—64%—were tested following at least one line of prior therapy; 48% of patients were tested after failure of first-line therapy.
Somatic tissue testing was more frequently conducted than liquid biopsy; among patients who were tested, 31.7% (n = 187) were HRR mutation–positive, including 11.2% (n = 21) of patients who had germline testing, 73.8% (n = 138) of those who had somatic testing, 2.1% (n = 4) of those who had both somatic and germline testing, and 12.8% (n = 24) of patients whose mutational status was unknown.
Not all the genetic assays used in study participants included the 14 HRR genes indicated in the FDA’s approval of olaparib. HRR mutations were most commonly detected in the ATM, BRCA2, CHEK2, and CDK12 genes. Circulating tumor DNA was analyzed with somatic liquid biopsy testing.
Among patients with metastatic castration-resistant prostate cancer whose disease was HRR mutation–positive, 66.8% (n = 125) received treatment with a PARP inhibitor.
Ultimately, these findings highlight the need for improved use of germline and somatic testing for this patient population as well as the potential negative impact on therapy choice if testing is skipped.
