Olaparib monotherapy shows benefit in HRR+ biochemically recurrent prostate cancer
“This study is a breakthrough because it is the first trial to show that a non-hormonal drug can induce durable complete remissions in recurrent prostate cancer patients with BRCA2 mutations—one of the most aggressive subtypes of this disease,” says Emmanuel S. Antonarakis, MD.
Olaparib (Lynparza) without accompanying androgen deprivation therapy demonstrated favorable clinical activity in the treatment of patients who have biochemically recurrent prostate cancer following radical prostatectomy and homologous recombination repair (HRR) gene alterations, according to data from a phase 2 trial (NCT03047135) published in JAMA Oncology.1
The median PFS was 22.1 months in the HRR-positive cohort, compared with 12.8 months in the HRR-negative cohort.
“This study is a breakthrough because it is the first trial to show that a non-hormonal drug can induce durable complete remissions in recurrent prostate cancer patients with BRCA2 mutations—one of the most aggressive subtypes of this disease,” said senior author Emmanuel S. Antonarakis, MD, an associate director of translational research at the University of Minnesota Masonic Cancer Center, Minneapolis and an adjunct professor at Johns Hopkins University, Baltimore, Maryland, in a news release on the findings.2 “It is a true paradigm shift, because now we can offer a non-hormonal precision therapy to these patients that is safe and effective while avoiding the side effects caused by hormonal deprivation.”
Overall, data showed that 13 patients (26% from total cohort), all within the HRR-positive cohort (48% in HRR-positive cohort), achieved a prostate-specific antigen (PSA) decline of at least 50% from baseline (PSA50). This included all 11 patients with a BRCA2 alteration. The other 2 PSA50 responses were seen among patients with a CHEK2 mutation and an ATM mutation. The median duration of response was 25 months overall.
No patients in the HRR-negative cohort experienced a PSA50 response.
The median progression-free survival (PFS) was 19.3 months among all patients included in the study. In the HRR-positive cohort, the median PFS was 22.1 months, compared with 12.8 months in the HRR-negative cohort. The median metastasis-free survival was 32.9 months overall. In the HRR-positive cohort, the median metastasis-free survival was 41.9 months vs 16.9 months in the HRR-negative cohort. Additionally, the median time to next anti-cancer therapy was 15.4 months overall, 22.7 months in the HRR-positive cohort, and 2.4 months in the HRR-negative cohort.
Regarding safety, the most common adverse events were fatigue (n = 32; 63%), nausea (n = 28; 55%), and leukopenia (n = 22; 43%).
In total, the single-arm, nonrandomized trial enrolled 51 men across 4 clinical trial sites in the United States. The median age of participants was approximately 64 years (SD, 6.8), with a median baseline PSA of 2.8 ng/mL. The HRR-positive cohort included 27 patients (53%), with BRCA2 alterations being the most common (n = 11). Six patients each had alterations in the CHEK2 and ATM genes.
To be eligible for the trial, patients needed to have biochemically recurrent prostate cancer following radical prostatectomy, a PSA doubling time of 6 months or shorter, an absolute PSA value of 1.0 ng/mL or higher, and a testosterone level of 150 ng/dL or higher.
Those included in the study received 300 mg oral olaparib twice daily until doubling of baseline PSA, clinical or radiographic progression, or unacceptable toxicity. The primary end point for the study was a confirmed PSA50 response. The secondary end points for the trial were outcomes by HRR alteration status and safety and tolerability.
Overall, the authors concluded, “Olaparib warrants further study as a treatment strategy for some patients with [biochemically recurrent] prostate cancer but does not have sufficient activity in those without HRR alterations and should not be considered for those patients.”1
References
1. Marshall CH, Teply BA, Lu J, et al. Olaparib without androgen deprivation for high-risk biochemically recurrent prostate cancer following prostatectomy: A nonrandomized controlled trial. JAMA Oncol. 2024. doi:10.1001/jamaoncol.2024.3074
2. Precision drug olaparib may be effective without hormone therapy for some men with biochemically recurrent prostate cancer. News release. Johns Hopkins Medicine. August 20, 2024. Accessed August 22, 2024. https://www.newswise.com/articles/precision-drug-olaparib-may-be-effective-without-hormone-therapy-for-some-men-with-biochemically-recurrent-prostate-cancer
