New findings support for the first time the use of routine tumor testing for homologous recombination repair (HRR) gene alterations in men with metastatic castration-resistant prostate cancer (mCRPC), investigators concluded in a presentation at the European Society for Medical Oncology (ESMO) 2019 Congress in Barcelona, Spain.

Using an investigational test, Johann de Bono, MD, of The Institute of Cancer Research and Royal Marsden, London, UK, and colleagues prospectively screened 4425 patients with mCRPC for qualifying HRR gene alterations in tumor tissue to determine eligibility for the phase 3 PROfound trial. Consistent with other studies, Dr de Bono’s team found a qualifying HRR alteration in 27.9% of the 2792 patients who had a successful tumor test result.

The PROfound trial compared the efficacy and safety of olaparib, a poly-ADP ribose polymerase (PARP) inhibitor, with enzalutamide or abiraterone (prescribed at a physician’s discretion) in 387 pre-treated men with mCRPC and a qualifying HRR gene alteration. Results showed that olaparib slowed cancer progression by about 4 months compared with enzalutamide or abiraterone. In addition, olaparib-treated patients experienced decreased time to pain progression and a higher objective response rate compared with enzalutamide or abiraterone recipients

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Dr de Bono and his collaborators pointed out that tissue testing can be challenging in prostate cancer due to insufficient tissue for gene panel testing. In their study, 31% of patients tested did not receive a biomarker test result because the samples did not meet pathology requirements or because of insufficient yields of extracted DNA.

In the current study, HRR gene alterations most commonly occurred in the BRCA2 gene, followed by CDK12 and ATM genes. The distribution of alterations in HRR genes within the randomized population reflected that observed in the screened population, according to the investigators. A co-occurring alteration in more than 1 HRR gene was detected in only 2.1% of the cases (59 out of 2,792 patients whose tissue samples were successfully sequenced), 7.6% of screened patients with a qualifying gene alteration (59 out of 778), and 7.2% of randomized patients (28 out of 387). “Future analyses are warranted to help understand if there are any correlations between clinical and demographic characteristics and HRR gene alterations, including germline versus somatic and mono- versus biallelic alterations,” concluded the authors.

All the men had documented tumor tissue qualifying mutation(s) in 1 of 15 HRR genes that was predicted to be deleterious or suspected deleterious. The 15 genes included gene alterations directly or indirectly associated with HRR (BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L).

Nancy Dawson, MD, an attending oncologist at the Prostate Cancer Research and Treatment Center at Georgetown University, Washington, DC, said the study is important because it provides the largest prospective look at HRR gene alterations in men with metastatic prostate cancer. “All men with metastatic disease should have their prostate cancer tissue tested for HRR gene alterations,” Dr Dawson told Renal & Urology News.

The efficacy and safety results from the PROfound trial, which also were presented at ESMO conference, showed that men treated with olaparib had significantly longer disease control than those treated with a second-generation hormone therapy (abiraterone or enzalutamide). Olaparib, an oral drug, only works in patients with certain altered DNA repair genes. “The only way to know that is to send the tissue for molecular analysis,” Dr Dawson said.

Tina Mayer, MD, a medical oncologist in the Prostate Cancer Program at Rutgers Cancer Institute and Assistant Professor of Medicine at Rutgers Robert Wood Johnson Medical School in New Brunswick, New Jersey, said emerging data in recent years regarding the role of genomic profiling have paved the way toward the use new targeted therapies, specifically PARP inhibitors. “Based on data from smaller prior studies, many providers have already been seeking treatment options with PARP inhibitors via clinical trials or appealing for off-label use of the drugs. The PROfound study will have a key impact on the management of patients with mCRPC,” Dr Mayer said.

As the field of oncology continues to evolve with newer and typically very expensive treatment options, she said, the ability to select patients for specific treatments based on genomic profiling will become increasingly important. There are also potential implications for genetic counseling of family members if testing identifies potential germline mutations, Dr Mayer noted.

“The study has clearly identified which patients have defective DNA repair genes or not, and so we will be able to look at the effect of the drug olaparib in situations where one would expect a response or not,” said Ameae M. Walker, PhD, Professor of Biomedical Sciences at the University of California, Riverside. The study’s inclusion of men from 20 countries, including the United States and countries in Europe and Asia, is an important study strength. “The more patients, the stronger and therefore more broadly applicable the data,” Dr Walker said.

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Benjamin Miron, MD, a hematology and oncology fellow at Fox Chase Cancer Center in Philadelphia, commended Dr de Bono’s team effort in characterizing the frequency of HRR mutations. “However, the failure rate of sequencing was rather high in this study,” Dr Miron said. “To improve outcomes, further analysis and discussion are needed to analyze the potential difference in response between patients with BRCA, ATM, and other HRR alterations.”

Moreover, it may be advantageous to look at co-occurring mutations in these patients using a broad sequencing panel to understand the influence of mutations outside of the realm of homologous recombination repair, he said. Further analyses may also help identify new avenues of treatment for the non-responders in this current trial.


De Bono J, Fizazi K, Saad F, et al. Central, prospective detection of homologous recombination repair gene alterations in tumour tissue from >4000 men with metastatic castration-resistant prostate cancer screened for the PROfound study.  Presented at the European Society for Medical Oncology 2019 Congress held September 27 to October 1 in Barcelona, Spain. Poster 847PD