AstraZeneca's Lynparza (olaparib) is showing promise as a non-hormonal therapy for recurrent prostate cancer in patients with homologous recombination repair (HRR) gene mutations, according to a Phase II trial. The study, published in JAMA Oncology, suggests that Lynparza could offer an alternative to androgen deprivation therapy (ADT), which often causes life-altering side effects.
The Need for Alternative Therapies
Following initial surgery and radiotherapy for localized prostate cancer, up to 40% of patients experience recurrence, indicated by rising prostate-specific antigen (PSA) levels. The standard treatment, ADT, suppresses testosterone production, leading to side effects such as low libido, erectile dysfunction, weight gain, and decreased muscle mass. Cathy Handy Marshall, an assistant professor at Johns Hopkins University, is exploring non-hormonal alternatives like Lynparza.
Lynparza's Efficacy in HRR-Mutated Prostate Cancer
The trial evaluated Lynparza's activity in 51 patients with recurrent prostate cancer post-prostatectomy. To be eligible, patients needed a PSA doubling time of six months or less, a PSA of at least 1.0 ng/mL, and a testosterone level of 150 ng/dL or higher. Patients received 300 mg of Lynparza twice daily until PSA doubling, radiographic progression, or unacceptable side effects.
The primary outcome was PSA response, with secondary outcomes including progression-free and metastasis-free survival. The study focused on patients with mutations in HRR genes, including ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCA, FANCE, PALB2, RAD51B, RAD51C, and RAD51D.
Significant Response in BRCA2-Altered Patients
Of the 51 patients, 27 had HRR mutations and 24 did not. Thirteen patients responded to Lynparza, all of whom had HRR mutations. Notably, all 11 patients with BRCA2 alterations responded. The other two responders had CHEK2 and ATM mutations. There were no responses among HRR-negative patients.
The median progression-free survival was 19.3 months overall, with 22.1 months in the biomarker-positive group and 12.8 months in the biomarker-negative group. Median metastasis-free survival was 32.9 months overall, 41.9 months in the biomarker-positive group, and 16.9 months in the biomarker-negative group.
Implications for Treatment Strategies
The study authors noted the 100% response rate in BRCA2-altered patients was higher than the 50-60% seen with Lynparza and hormonal suppression in other studies. This suggests that earlier treatment with Lynparza, before ADT-induced tumor heterogeneity, may improve response rates. Emmanuel Antonarakis from the University of Minnesota's Masonic Cancer Center highlighted that this is the first study to show complete remissions with a non-hormonal drug in recurrent prostate cancer patients with BRCA2 mutations.
Handy Marshall emphasized that not all prostate cancer patients need hormone therapy and that Lynparza appears ineffective in those without HRR mutations. Follow-up studies are planned to confirm these findings and explore the mechanisms of therapy response in HRR-deficient patients, focusing on biomarker-selected populations.
