Implementation of routine tumor genetic testing may help identify the approximately 30% of men with metastatic castration-resistant prostate cancer (mCRPC) who may significantly benefit from targeted treatment, namely PARP inhibitors, an international study suggests.
The results were presented in a poster, titled “Central, prospective detection of homologous recombination repair gene mutations (HRRm) in tumour tissue from >4000 men with metastatic castration-resistant prostate cancer (mCRPC) screened for the PROfound study,” at the European Society for Medical Oncology (ESMO) Congress 2019 that recently took place in Barcelona, Spain.
Tumors of men with mCRPC can have damaging mutations in a variety of genes, including those involved in the process of homologous recombination (HR) in DNA repair. Among HR gene mutations, those in the BRCA1, BRCA2, and ATM genes are the most common, and they have been shown to be sensitive to PARP inhibitors in ovarian and breast cancer.
PARP inhibitors selectively block the activity of the PARP enzyme, which acts as a DNA damage sensor, binding to the sites of DNA damage and leading to its repair.
This type of treatment has been found to be particularly effective in cancer cells with defects in other DNA repair pathways — such as those with BRCA and ATM mutations — thus relying on PARP to survive and proliferate. This way, PARP suppression leads to the accumulation of DNA damage and ultimately to the death of these cancer cells.
Interim results from the PROfound Phase 3 study (NCT02987543) — also presented at the ESMO congress — showed that Lynparza (olaparib), a PARP inhibitor, significantly delayed cancer progression in mCRPC patients with HR mutations, compared to standard treatment with Xtandi (enzalutamide) or Zytiga (abiraterone).
These benefits were seen in patients with mutations in BRCA1, BRCA2, or ATM genes, which was the study’s main goal.
Lynparza is an oral anti-cancer treatment developed by AstraZeneca and Merck (known as MSD outside the U.S. and Canada) and approved for the treatment of advanced forms of ovarian and breast cancer with BRCA mutations.
The international, randomized, open-label PROfound trial compared the safety and efficacy of Lynparza to that of Xtandi or Zytiga (prescribed at a physician’s discretion) in 387 pre-treated men with mCRPC and a mutation in one of 15 HR genes.
Participants were recruited at 21 countries, including the U.S. and countries in Europe and Asia.
Johann de Bono, MD, head of the division of clinical studies at The Institute of Cancer Research in London, U.K., and colleagues used the FoundationOne CDx test, which was developed in collaboration with Foundation Medicine, to select mCRPC patients with qualifying HR gene mutations in their tumors for the PROfound trial.
Among the 4,047 patients whose tumor samples were tested, 2,792 (69%) had an interpretable result, and 778 of them (27.9%) had a qualifying HR mutation. This value was consistent with other studies estimating that 20% to 30% of mCRPC patients have HR mutations, whether inherited or developed during their lifetime.
In these patients, the most common HR gene alterations occurred in the BRCA2 gene, followed by the CDK12 and ATM genes. A total of 59 patients (7.6%) had a co-occurring mutation in more than one HR gene, which was most commonly found in patients with BRCA2, CDK12, or ATM mutations.
“This is the largest study to date with central prospective [HR mutations] tissue testing in prostate cancer,” the researchers wrote.
Besides having a qualifying HR gene alteration, the 387 patients who met the remaining eligibility requirements of the trial entered the study and were divided into two groups according to the presence of mutations in the BRCA1, BRCA2, and ATM genes (245 patients) or in one of the other 12 HR genes (142 patients).
The PROfound study’s interim results showed that Lynparza targeted treatment significantly delayed disease progression and associated pain, extended survival, and induced responses in a higher proportion of patients over standard treatment in the group of patients with BRCA1, BRCA2, or ATM genes.
Analysis on the overall population of patients (both patient groups) suggested that those with mutations in the other 12 HR genes also benefited more from Lynparza treatment than from standard treatment, but to a lesser extent.
The trial’s final results and additional exploratory analysis may help to clarify the potential difference in response to Lynparza between these two groups of patients.
“Further analyses are warranted to help understand if there is any correlation between clinical/demographic characteristics and [HR mutations],” the researchers said.
Of note, the study was funded by AstraZeneca and MSD.