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Platinum-based chemotherapy shows efficacy in BRCA2-mutated prostate cancer
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A small group of men with metastatic, castration-resistant prostate cancer who carried a BRCA2 mutation responded favorably to platinum-based chemotherapy normally used in the treatment of breast and ovarian cancers, according to a retrospective analysis published in Cancer.
“The recent identification of the importance of the DNA repair pathway in a subset of men with prostate cancer provided the impetus for this study,” Matthew L. Freedman, MD, and Mark Pomerantz, MD, associate professors of medicine at Dana-Farber Cancer Institute, told HemOnc Today, referring to a 2015 study by Mateo and colleagues published in The New England Journal of Medicine. “PARP inhibitors demonstrated therapeutic efficacy in men harboring both germline and somatic mutations in the DNA repair pathway.
“Other tumor types — most notably breast and ovarian cancers — have demonstrated a sensitivity to both PARP inhibitors and platinum-based reagents,” Freedman and Pomerantz added. “Therefore, we hypothesized that men carrying mutations in the DNA repair pathway would be more sensitive to platinum-based chemotherapy compared with noncarriers.”
From 2001 through 2015, a subgroup of 141 men with metastatic, castration-resistant prostate cancer (mean age, 59 years; 94% taxane refractory) received at least two doses of carboplatin in combination with docetaxel (range, 60-75 mg/m2) every 3 weeks.
Researchers used DNA sequencing to identify patients who harbored BRCA2 mutations (n = 8; 5.7%) and those who did not (n = 133; 94.3%). Response rate to carboplatin/docetaxel chemotherapy — defined as a decline in PSA that exceeded 50% within 12 weeks of regimen initiation — served as the primary endpoint.
Six of the eight BRCA2 carriers (75%) experienced PSA declines greater than 50% within 12 weeks, with two men experiencing declines of 90%.
Comparatively, 23 of 133 noncarriers (17%; absolute difference, 58%; 95% CI, 27-88; P = .001) experienced PSA declines greater than 50%.
Most patients (n = 133) died of prostate cancer. Median survival from initiation of carboplatin/docetaxel was 10.2 months. A PSA response greater than 50% increased median survival to 16.4 months; no PSA response or a response less than 50% decreased median survival to 9.4 months.
“We were encouraged that the response rate among BRCA2 carriers in our prostate cancer cohort was quite profound,” Freedman and Pomerantz said. “The findings suggest that there is an accessible, effective regimen for a subset of patients with a very aggressive and advanced form of the disease.”
A 2009 phase 3 study by Sternberg and colleagues, published in Journal of Clinical Oncology, showed no OS benefit for satraplatin (JM-216, GPC Biotech), an oral platinum analog. Therefore, platinum is not routinely used in the management of men with prostate cancer, Freedman and Pomerantz said.
“Our findings suggest that the subset of men who carry DNA repair mutations may, in fact, benefit from platinum agents,” they added. “These data reinforce the concept of personalized medicine where clinical decision-making is informed by a particular variable that is not evenly distributed through the patient population.”
Researchers noted that although their results suggest a survival advantage for men with BRCA2-associated metastatic, castration-resistant prostate cancer who receive treatment with carboplatin in combination with docetaxel, the small size of the study does not allow for definitive conclusions, and a study comparing PARP inhibitors to platinum-based agents is warranted.
A previous study showed the efficacy of olaparib (Lynparza, AstraZeneca) — a PARP inhibitor —in men with BRCA2-associated metastatic, castration-resistant prostate cancer, Michael S. Humeniuk, MD, Tian Zhang, MD, and Andrew J. Armstrong, MD, ScM, from the department of medicine at Duke University Medical Center, wrote in an accompanying editorial. Humeniuk and colleagues also referenced their own study, which showed positive responses to platinum-based therapy.
“Overall, these data suggest that a subset of men with prostate cancer do respond well to platinum-based chemotherapy and that one such responsive group includes men who harbor BRCA2 germline mutations,” Humeniuk, Zhang and Armstrong wrote. “It is noteworthy that, in their study, nearly 20% of men without such mutations still responded to carboplatin, and these men may have harbored somatic mutations in DNA repair genes.” – by Chuck Gormley
For more information:
Matthew L. Freedman, MD, can be reached at Dana-Farber Cancer Institute, Molecular and Cellular Oncology-Dana 710A, 44 Binney St., Boston, MA 02115; email: mfreedman@partners.org.
Mark Pomerantz, MD, can be reached at Dana-Farber Cancer Institute, Medicine, Dana Building Room 1230, Boston, MA 02215; email: mpomerantz@partners.org.
Disclosure: Rebecca and Nathan Milikowsky and the H.L. Snyder Medical Foundation funded this study. The researchers report no relevant financial disclosures. Humeniuk reports he has no relevant financial disclosures. Please see the editorial for a list of all other authors’ relevant financial disclosures.
References:
Mateo J, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1506859.
Sternberg CN, et al. J Clin Oncol. 2009;doi:10.1200/JCO.2008.20.1228
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