Progress in HRR testing for prostate cancer

Testing for homologous recombination repair mutations (HRRm) in prostate cancer is increasingly important for guiding management and treatment decisions.¹

There is a need for clear guidance on HRR testing in prostate cancer

There is general agreement between the available guidelines and consensus statements that all men with metastatic prostate cancer (mPC) should have somatic (tumor) testing for HRR and mismatch repair (MMR) gene mutations, as illustrated in Figure 1. But other recommendations on whom, when and what to test are not yet fully aligned, some guidelines are out of date, and others are yet to include HRR testing at all: clear and consistent recommendations for genetic profiling represent a current unmet need in metastatic castration-resistant prostate cancer (mCRPC).

Figure 1. Brief overview of HRR testing recommendations from selected current guidelines.^2-5 AUA, American Urological Association; DDR, DNA damage response; EAU, European Association of Urology; ESMO, European Society for Medical Oncology; mCRPC, metastatic castration-resistant prostate cancer; mCSPC, metastatic castration-sensitive prostate cancer; MMR, mismatch repair; mPC, metastatic prostate cancer; NCCN, National Comprehensive Cancer Network; SUO, Society of Urologic Oncology.

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Despite testing for homologous recombination repair mutations (HRRm) being recommended by guidelines, access to testing remains uneven, with some groups underserved.¹ In a clinical trial of patients with metastatic castration-sensitive prostate cancer (mCSPC), Black patients had similar survival outcomes to White patients² – yet in the USA, they are twice as likely to die of PC.^2,3 Patients with mPC who are Black, Hispanic, Latino, or have low socioeconomic status are significantly less likely to have next-generation sequencing (NGS) testing compared with White patients.¹

Inconsistencies in attitudes and access to HRR testing leave some patient groups underserved

Two recent surveys evaluated real-world testing patterns and identified more barriers to equitable testing.^4,5

Castro et al. (2023) surveyed 222 physicians who provided information for 1,816 patients with metastatic castration-resistant PC (mCRPC) in the EU5 countries (France, Germany, Italy, Spain, UK).⁴

• 670 patients (37%) were tested for HRRm
• 71% of the 670 tested patients were tested only for BRCA1/2, and the remaining 29% for BRCA1/2 plus other HRR genes
• Testing rates ranged from 12% in the UK to 49% in Germany

Leith et al. (2022) looked at HRRm testing patterns for 391 physicians and 1,913 patients in the EU5, the USA, and Japan.⁵

• The proportion of physicians who tested ranged from 72.2% in the USA to 26.2% in Japan
• Within the EU5, Germany had the most testers (80.0%) and the UK had the fewest (35.1%)
• 90.3% of physicians in the USA and 94.0% in Germany had access to testing, versus 56.6% in Japan and 48.6% in the UK

In both surveys, the most common reason for not testing was high cost. This was followed by problems accessing the latest tests, lack of reimbursement, lack of physician awareness of testing, time taken to get results, and testing not being recommended in local guidelines. Other important reasons included no facility for in-house testing, not being comfortable in interpreting results, and lack of adequate sample.^4,5

In both surveys, the patients most likely to receive testing had a known family history of PC or breast, ovarian, or pancreatic cancer. Others had an initial diagnosis of locally advanced disease, failure to respond to hormone therapy or chemotherapy, high-risk disease, surgery to treat their PC, or young age at diagnosis.^4,5 Conversely, Castro et al. reported that patients were less likely to be tested if they were over 70 years old at the time of data collection.

Finally, poly (ADP-ribose) polymerase inhibitors (PARPi) were approved during data collection by Leith et al., so they asked about the impact of availability on the physicians’ testing decisions. Just over half of physicians in the USA and Japan, and 80% of those in the EU5, said they would be more likely to test for HRRm if a PARPi was available.⁵

Testing rates in the USA did increase after PARPi approval, from 15% in the first 5 months of 2020 to 62% in the 14 months to the end of 2021.⁶ However, a third of HRRm-positive patients still did not receive PARPi.⁶ This lack of comprehensive testing and treatment highlights a major unmet need.

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Good-quality samples are key to obtaining usable HRR test results

The first step for targeted therapy is to identify the appropriate gene alterations. Next-generation sequencing (NGS) can identify multiple genes per sample, subject to high-quality tumor tissue samples.¹ Tumor testing fails up to 40% of the time,^1,2 most often due to inadequate specimen (less than 20% tumor content or insufficient tumor nuclei; tissue volume less than 0.2 mm³) or insufficient DNA yield or quality (age of sample or other DNA degradation problem).^1,3 In the PROfound study, 58% of samples produced results for 69% of patients. Most samples were from archival primary prostate tissue. Evaluation of sample characteristics showed that better results were obtained from those that:¹

• Were newly obtained, rather than archival (gradual decline in success with increasing sample age)
• Had total tissue volume ≥0.6 mm³; radical prostatectomy and transurethral resection of the prostate (TURP) produced more results than prostate core needle biopsy (CNB)
• Had increased total tumor content (for increased DNA yield), preferably from metastatic lymph node tissue rather than primary tissue or bone samples

Overall, DNA yield was higher with newer, non-prostate tissue compared with archival and primary samples.¹ The authors recommended standard formalin fixation of newly collected samples, and not using decalcification on bone samples.¹

Aside from variable sample quality, additional limitations of tumor testing are the challenges of biopsy in less accessible metastases, intra-patient and tumor heterogeneity that may result in missed/incorrectly classified cancer, and the impracticality of repeat biopsies to monitor tumor evolution and treatment responses.⁴ An alternative option is liquid biopsy (LB) for circulating tumor DNA (ctDNA), which can be used to test for germline and somatic alterations.²

Studies comparing tumor tissue biopsy and LB found that ctDNA was evaluable in 92–100% of patients, versus 68–88% of tumor tissue samples.^5,6 Mandel et al. (2024) found that LB identified more patients with BRCA1/2 mutations.⁶ However, there were false negatives with each test type, showing that using a combined testing strategy would give the highest chance of identifying homologous recombination repair (HRR) alterations.^5,6 A comparison of the two methods is shown in Figure 1.

Figure 1. Comparison of advantages and disadvantages of solid biopsy and liquid biopsy for prostate cancer diagnosis. A combination of both methods may give best results^7,8. ctDNA, circulating tumor DNA.

LB can be useful in cases where NGS on tumor tissue has failed, metastatic tissue collection is not possible, or there is no access to tumor testing.² LB could be used for repeat biopsy, biopsy at disease progression and for bone metastasis, and could help assess tumor heterogeneity.⁶ It is less invasive and more easily repeatable than tissue biopsy, allowing continual updates, and is usually cheaper and faster.⁸ Downsides are that LB may fail to detect early disease with low ctDNA concentration, possibly delaying appropriate treatment, and that differing rates of shedding from tumors may lead to an inaccurate clinical picture of heterogeneity.^4,8 Lastly, there is still a need for validated sampling guidelines and protocols for use of LB in management of metastatic castration-resistant prostate cancer.