Olaparib may be effective in treating men with biochemically recurrent prostate cancer without accompanying hormone therapy, according to a novel study published by Marshall et al in JAMA Oncology.
Background
Although most men with localized prostate cancer can be cured with surgery or primary radiotherapy, up to 40% of them will experience a biochemical recurrence of their cancer, indicated by rising prostate-specific antigen (PSA) levels.
A common treatment approach for recurrent prostate cancer is androgen-deprivation therapy, which is designed to inhibit testosterone production. However, many men forgo androgen-deprivation therapy because the lack of testosterone can lead to side effects such as hot flashes, fatigue, or weight gain.
“We have done a number of trials looking for therapies for prostate cancer that are not hormone suppressing to avoid those side effects,” explained lead study author Cathy Handy Marshall, MD, PhD, Assistant Professor of Oncology at Johns Hopkins University.
The PARP inhibitor olaparib is approved by the U.S. Food and Drug Administration for the treatment of metastatic prostate cancer in combination with hormone therapy. However, whether the drug could be effective without the accompanying hormonal suppression was unknown.
Study Methods and Results
In this phase II clinical trial, researchers enrolled 51 men with a mean age of 64 years who had biochemically recurrent prostate cancer following radical prostatectomy, as measured by high PSA levels, between May 2017 and November 2022. The patients were then assigned to receive 300 mg of oral olaparib twice daily without hormonal suppression until their baseline PSA level doubled, their cancer worsened as determined by imaging or other signs or symptoms, or they had unacceptable treatment-related side effects or toxicity. The duration of treatment varied, and in some cases, the patients received therapy for over 2 years.
Among the patients, 53% (n = 27) of them were considered biomarker positive and presented with genetic mutations that were more likely to make their tumors sensitive to olaparib. The patients had median baseline PSA levels of 2.8 ng/mL, and most of them had Gleason Grade Group 3 and above disease. The researchers noted that 86% of the patients had received radiotherapy following surgery. In those with positive biomarkers, BRCA2 mutations (n = 11) were the most common followed by ATM mutations (n = 6) and CHEK2 mutations (n = 6).
About 50% (n = 13/27) of the patients in the biomarker-positive group had a decrease in PSA levels of 50% or greater, including all 11 patients with BRCA2-mutated prostate cancer, indicating that their cancer was diminishing.
The median duration of response was 25 months. The other two PSA responses were seen in the patients with CHEK2- and ATM-mutated disease. No PSA responses were seen among the 24 patients in the biomarker-negative group, demonstrating that olaparib should not be considered in these patients.
The median PSA progression-free survival was 19.3 months overall and 22.1 months in the biomarker-positive group compared with 12.8 months in the biomarker-negative group. The median metastasis-free survival was 32.9 months overall and 41.9 months in the biomarker-positive group vs 16.9 months in the biomarker-negative group.
Additionally, the median time to next anticancer therapy was 15.4 months overall and 22.7 months in the biomarker-positive group compared with just 2.4 months in the biomarker-negative group.
The researchers reported that the most common adverse events in the patients who received olaparib were fatigue, nausea, and leukopenia.
Conclusions
“This study is a breakthrough because it is the first trial to show that a nonhormonal drug can induce durable complete remissions in [patients with BRCA2-mutated] recurrent prostate cancer—one of the most aggressive subtypes of this disease,” emphasized senior study author Emmanuel Antonarakis, MD, Associate Director of Translational Research at the University of Minnesota Masonic Cancer Center and Adjunct Professor at Johns Hopkins University. “It is a true paradigm shift because now we can offer a nonhormonal precision therapy to these patients that is safe and effective while avoiding the side effects caused by hormonal deprivation,” he highlighted.
Disclosure: The research in this study was supported by AstraZeneca, Foundation Medicine, and Veracyte and in part by the National Cancer Institute, National Institutes of Health, the V Foundation, the Robert A. Winn Career Development Award, the Prostate Cancer Foundation, and the U.S. Department of Defense. For full disclosures of the study authors, visit jamanetwork.com.
