The cancer treatment drug olaparib shows promise in addressing biochemically recurrent prostate cancer without the need for hormone therapy in men carrying mutations in genes like BRCA2, based on findings from a phase II clinical trial involving 51 patients.
The cancer treatment olaparib appears to be beneficial for men with biochemically recurrent prostate cancer, particularly those with mutations in genes like BRCA2, and it may not require hormone therapy, according to a phase II clinical trial conducted with 51 participants at Johns Hopkins Kimmel Cancer Center and three other institutions.
The research focused on men who showed signs of cancer recurrence after prostate surgery, indicated by elevated levels of prostate-specific antigen (PSA). After receiving olaparib, 13 patients, including all 11 with BRCA2 mutations, experienced a decrease in PSA of at least 50%—a positive sign that their cancer was diminishing.
The findings were published on August 22 in JAMA Oncology. Other sites involved in the study included the University of Nebraska Medical Center in Omaha, the Allegheny Health Network Cancer Institute in Pittsburgh, and Thomas Jefferson University Hospital in Philadelphia.
While surgical procedures or primary radiotherapy can cure many men with localized prostate cancer, up to 40% may see a rise in PSA, indicating recurrence, explains Dr. Cathy Handy Marshall, lead author of the study and an assistant professor of oncology at Johns Hopkins. The study was also co-led by Dr. Emmanuel Antonarakis, an expert in prostate cancer, who currently serves as associate director of translational research at the University of Minnesota Masonic Cancer Center, while keeping an adjunct professorship at Johns Hopkins.
Androgen deprivation therapy, a typical treatment for recurrent prostate cancer, involves medication aimed at inhibiting testosterone production. However, many men find this treatment undesirable due to side effects like hot flashes, fatigue, or weight gain, Marshall notes.
“We’ve conducted several trials to find prostate cancer treatments that do not suppress hormones to avoid these side effects,” she adds.
Olaparib, a targeted cancer drug that intercepts the protein PARP from repairing damaged DNA, is approved by the U.S. Food and Drug Administration for treating metastatic prostate cancer alongside hormonal therapy. However, its effectiveness without hormonal suppression was previously unknown, according to Marshall.
The trial enrolled 51 patients from May 2017 to November 2022. Each participant had biochemically recurrent prostate cancer following radical prostatectomy (surgery to remove the prostate, seminal vesicles, and nearby lymph nodes). Of these participants, 27 (53%) were classified as biomarker-positive, meaning they had specific gene mutations that could make them more responsive to olaparib. The average age of patients was around 64 years, with a median baseline PSA of 2.8 nanograms per milliliter. Most had Gleason Grade Group 3 or higher, indicating high-grade cancer. Approximately 86% had undergone radiotherapy post-surgery. The most commonly altered gene among biomarker-positive patients was BRCA2 (11 patients), followed by ATM and CHEK2 genes (six patients each).
Participants received 300 milligrams of olaparib orally twice daily (without hormonal therapy) until their baseline PSA levels doubled, they exhibited cancer progression determined by imaging, or they experienced intolerable side effects. The treatment duration varied significantly; some patients remained on therapy for over two years, according to Marshall.
In the biomarker-positive group, around half (13 out of 27) had a PSA reduction of 50% or more, including all 11 with BRCA2 mutations. The median response duration was 25 months. Additionally, two PSA reductions were noted in participants with CHEK2 and ATM mutations. No PSA improvements were seen among the 24 biomarker-negative individuals, leading the authors to recommend against this therapy for that group in the future.
The median PSA progression-free survival was 19.3 months overall, with 22.1 months in biomarker-positive individuals, compared to 12.8 months in those who were biomarker-negative. The median metastasis-free survival was 32.9 months overall and 41.9 months in the biomarker-positive group, as opposed to 16.9 months for biomarker-negative participants.
The median interval before requiring another anti-cancer therapy was 15.4 months overall, with 22.7 months in biomarker-positive individuals vs. only 2.4 months in the biomarker-negative group.
Common side effects of olaparib included fatigue, nausea, and leukopenia (a reduction in infection-fighting white blood cells).
“This study represents a significant advancement as it is the first to demonstrate that a non-hormonal medication can lead to lasting complete remissions in recurrent prostate cancer patients with BRCA2 mutations—one of the most aggressive forms of the disease,” says Antonarakis. “It marks a real transformation in treatment options, as we can now offer a safe and effective targeted therapy without the side effects associated with hormone deprivation.”
Co-authors of the study included Jiayun Lu, Lia Oliveira, Hao Wang, Channing Paller, Mark Markowski, Samuel Denmeade, Serina King, Rana Sullivan, Mario Eisenberger, Michael Carducci, and Tamara Lotan from Johns Hopkins. Additional contributors were from Veracyte in San Francisco.
The research received support from AstraZeneca, Foundation Medicine, and Veracyte. Marshall’s work was funded in part by the National Cancer Institute (grant P30 CA006973), the V Foundation, a Robert A. Winn Career Development Award, and the Prostate Cancer Foundation. Antonarakis received partial support from the National Institutes of Health/National Cancer Institute (grant P30 CA077598) and the Department of Defense (grant W81XWH-22-2-0025). Marshall also receives funding from Tempus, Dendreon, ObsEva, Astellas, MashupMD, and Community Health Marketing, all managed by The Johns Hopkins University according to its conflict-of-interest protocols.
