CRPC patients with DNA repair gene aberrations may benefit from platinum-based therapies
medwireNews: Platinum-based chemotherapy is active in patients with advanced castration-resistant prostate cancer (CRPC) and DNA repair gene alterations, shows a chart review.
“Genomic aberrations that impair DNA repair genes occur at a frequency of up to 20% to 30% in advanced prostate cancer,” and some of these alterations “have been associated with sensitivity to platinum compounds and/or PARP inhibition in preclinical studies and in clinical trials,” explain the researchers.
The team analyzed data pertaining to 508 patients with locally advanced or metastatic prostate cancer who were treated with a platinum compound (carboplatin, 88.8%; cisplatin, 10.8%; oxaliplatin, 0.4%) as a monotherapy (19.7%) or as part of a combination (80.3%) at one of 25 centers across 12 countries between 1986 and 2018. Over two thirds (67.1%) of patients had received at least one prior systemic therapy.
Thirty-five percent of patients underwent genomic profiling, and in total 15.7% of the study participants had DNA repair gene aberrations.
The prostate-specific antigen response rate (PSA, decrease ≥50%) was higher among the patients with DNA repair gene aberrations than those without aberrations, at 47.1% versus 36.1%, but the between-group difference did not reach statistical significance.
Similarly, the rate of soft tissue response – defined as a 30% or greater decrease in the sum of the longest diameter of all target lesions – was also numerically, but not significantly, greater among men with versus without alterations, with corresponding rates of 48.3% and 31.3%.
And median overall survival (OS), measured from the initiation of platinum-based therapy, was 14.1 months for patients carrying alterations and 9.2 months for those without, but again this difference was not significant.
Notably, PSA response rates differed significantly depending on the type of DNA repair gene aberration, with rates of 63.9%, 36.4%, 0.0%, and 28.6% for BRCA2, ATM, BRCA1, and other genes, respectively. A similar pattern was seen for OS, with corresponding median durations of 15.0, 9.3, 4.1, and 4.9 months. No significant between-group differences were observed for soft tissue responses.
Sabine Schmid (Princess Margaret Cancer Centre, Toronto, Ontario, Canada) and colleagues explain that “different DNA repair gene aberrations are most likely distinct entities with varying responses to platinum as well as PARP inhibition; therefore, they cannot be collectively addressed.”
They add: “More research with prospective trials in molecular subgroups is needed to better characterize which patients might derive benefit.”
Among the 65% of patients in this study who did not undergo genomic profiling the PSA response rate was 28.5%, the soft tissue response rate was 20.5%, and median OS was 10 months.
“This population is possibly most reflective of the general CRPC population seen in many centers around the world, where testing for DNA repair gene aberrations may not be available in daily clinical practice,” comment the researchers.
They write in JAMA Network Open that their data demonstrated “consistently higher response rates of platinum-based treatment in molecularly selected patients, even though these patients often received platinum-based monotherapy, which seems to be less active than combination therapy overall.”
Schmid et al conclude: “These results need prospective validation, which hopefully will be provided from the currently recruiting trials in molecularly selected prostate cancer populations.
“Based on our analysis, platinum-containing therapy should be considered in patients with DNA repair gene aberrations, especially if access to a PARP inhibitor is not available.”
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