Significance of Early Genetic Testing in HRR-Mutated mCRPC Highlighted by Real-World Observations

PC-3 human prostate cancer cells: © heitipaves - stock.adobe.com

An examination of real-world data involving individuals with metastatic castration-resistant prostate cancer (mCRPC) characterized by homologous recombination repair (HRR) mutations and treated with olaparib (Lynparza) underscored the importance of implementing earlier and more consistent genetic testing. This is crucial for enhancing precision in the treatment of this specific patient group, according to data from a real-world analysis presented at the 2024 Genitourinary Cancers Symposium.

The study garnered information from 192 patients from an electronic database, where investigators ultimately found that most patients evaluated in the study (74.0%) were tested at or following their mCRPC diagnosis; however, only 5.7% of these patients were tested prior to first-line treatment.

Upon further investigation, 36.1% of patients with any BRCA mutation (n = 108) had somatic only testing; 18.5% had germline only testing; 28.7% had germline and somatic testing; and 16.7% had other undetermined testing. Conversely, in the non-BRCA HRR mutation group (n = 84), 46.4% of patients had somatic only testing; 10.7% had germline only testing; 26.2% had both germline and somatic testing; and 16.7% had other undetermined testing.

In the any BRCA-mutated group, 75.9% of patients were tested at or following their diagnosis, and 3.7% of patients were tested prior to their first line of treatment. The median time from mCRPC diagnosis to testing was 20.7 months. In the non-BRCA HRR mutation group, 71.4% of patients were tested on or after their mCRPC diagnosis. The median time from diagnosis to biomarker test was 13.5 months, and 13.3% of these patients were tested prior to first-line treatment.

“HRR testing in patients before or at the time of mCRPC [diagnosis] would allow for olaparib therapy earlier in the disease course and potentially greater clinical benefit,” lead study author, Daniel J. George, MD, and colleagues, wrote in the poster presentation. “Based on an expanded FDA label, earlier testing will be needed in order to utilize olaparib with abiraterone in patients with BRCA mutations in the first line [in] mCRPC.”

George is the director of Genitourinary (GU) Oncology and a professor of medicine and surgery at Duke University School of Medicine, in Durham, North Carolina.

As nearly a quarter of patients with mCRPC display an HRR gene mutation, early germline and somatic testing continue to be recommended for this patient population. Notably, olaparib is one of the first available targeted therapies for these patients and has shown superior survival outcomes compared with physician’s choice of therapy.

Based on this information, investigators designed a study to assess both treatment patterns and the results of genetic testing in patients with HRR-mutated mCRPC who were previously treated with olaparib monotherapy.

To be eligible for this evaluation, patients must have had a confirmed HRR-mutated mCRPC diagnosis, be at least 21 years of age, and have received olaparib monotherapy treatment following exposure to abiraterone (Zytiga) or enzalutamide (Xtandi). Notably, an HRR mutation was defined as a mutation in at least 1 of the following genes: BRCA1, BRCA2, ATM, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L.

Exclusion criteria included a diagnosis of any other primary cancers or enrollment onto any other prior or current interventional clinical trial on or after mCRPC diagnosis. Notably, variables in patient demographics, clinical characteristics, and biomarker testing patterns were allowed in the patient population.

This retrospective, non-interventional study utilized electronic medical record data from the ConcertAI Oncology Dataset. This dataset included information from patients from geographically diverse locations primarily comprised of community oncology practices in the United States. Upon enrollment, patients were divided into 1 of 2 groups: any BRCA mutation vs non-BRCA HRR mutations.

Data collection began on February 7, 2023, and ended on June 16, 2023, and medical records from patients with a diagnosis date between 1990 to 2023,

The median age of all patients enrolled at the index date was 73 years. The majority of patients in the overall population were White (77.1%), and 68.2% did not identify as Hispanic or Latino. A total of 63.0% of patients had a known disease stage at initial diagnosis; 1.7% of these patients were classified as stage I, 15.7% were stage II, 9.1% were stage III, and 73.6% were stage IV.

Of the 141 patients with a documented ECOG performance status (PS), 76.6% had a PS of 0 or 1 vs 23.4% with a PS of 2 and greater. Notably, 88.8% of patients had distant metastasis in the bone at the index date.

Moreover, 77.6% of patients had a known Gleason score. Of these, 10.1% had a score of 6 or less, 24.2% had a score of 7, and 65.8% had a score of 8 or more. The median time from mCRPC diagnosis to the end of the patient’s record was 25.3 months; the median time from index date to end of record was 8.4 months; the median prostate-specific antigen value at index date plus or minus 30 days was 72.2 ng/mL; and 31.3% of patients indicated opioid usage at index date. Of the 145 patients with a known setting of care, 14.5% were treated in an academic setting and 85.5% were treated in a community setting.

In the poster presentation, researchers went on to note that 40.6% of patients underwent somatic only testing compared with 15.1% of patients who underwent germline only testing and 27.6% who underwent both germline and somatic testing. However, 16.7% of patients had received other undetermined testing.

Notably, the study authors disclosed multiple limitations of the investigation:

• The study was only conducted in patients who had received olaparib following prior enzalutamide or abiraterone treatment.
• The investigation exclusively comprised patients from the ConcertAI Oncology Dataset, which may differ from the overall mCRPC patient population.
• Most patients included in the study were treated in the community setting and all patients were treated in the United States.
• The analysis was limited to the extent of the data available in this dataset.
• Information on patients’ reasons for opioid usage was not collected.

Overall, this investigation emphasizes the need for earlier and more consistent testing for HRR mutations in patients with mCRPC.

“Most patients in this study were tested and diagnosed with an HRR mutation many months after their mCRPC diagnosis, at which point they had high levels of bone metastasis, multiple sites of distant metastases, and opioid use at the initiation of olaparib treatment with less likelihood of benefiting from a precision oncology approach,” the study authors concluded.

REFERENCE:

George DJ, Kariburyo-Yay F, Aggarwal H, et al. Real-world homologous recombination repair mutation (HRRm) testing patterns in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with olaparib in the United States. J Clin Oncol. 2024;42(suppl):332. doi:10.1200/JCO.2024.42.4_suppl.332