Olaparib Without ADT May Elicit High Response Rates in Prostate Cancer Subset

Postsurgical olaparib led to durable response rates in patients with high-risk biochemically recurrent prostate cancer with BRCA2 alterations.

Olaparib (Lynparza) monotherapy contributed to high and durable responses, defined as a 50% or greater decline in prostate specific antigen (PSA), in patients with high-risk biochemically recurrent prostate cancer after radical prostatectomy, as demonstrated by findings published in JAMA Oncology.

In this phase 2, multicenter, single-arm, nonrandomized-controlled trial, olaparib presented a PSA decrease of 50% or greater in 13 (26%) of the 51 patients, which represented 48% of patients in the homologous recombination repair-positive group (13 of 27). In addition, all 11 patients with BRCA2 alterations experienced this degree of response.

“If validated, these findings may be used to inform future, potential combination therapy approaches for patients with advanced prostate cancer without BRCA2-altered disease or with other non-BRCA2 [homologous recombination repair] alterations,” study authors wrote.

Additionally, 2 confirmed responses indicating at least a 50% decrease in PSA were observed in 1 patient with a CHEK2 alteration and a patient with an ATM alteration. Of note, PSA progression-free survival in the biomarker-positive group was 19.3 months vs 8.5 months in the biomarker-negative group (P < .001) in the sensitivity analysis using restricted mean survival time over 36 months.

These findings suggest further research focusing on olaparib as a treatment strategy for some patients with biochemically recurrent prostate cancer, however; those without homologous recombination repair alterations should not be considered for those patients, the study authors wrote.

Several adverse events occurred in patients included in the study such as fatigue (63%), nausea (55%), and leukopenia (43%). Researchers noted that these adverse effects were consistent with what is known of olaparib. There were also 2 serious adverse events during the study including anemia, which was related to the study drug, and a cerebrovascular accident, which was unrelated to the study drug.

This trial consisted of 51 male patients with a mean age of 63.8 years with a median baseline PSA of 2.8 ng/mL (range, 1.0-37.6). Of these patients, 27 (53%) had positive biomarker results. Gleason grade group 5 disease was noted in 11 of the 27 patients (41%) in the biomarker-positive group and 5 of the 24 patients (21%) in the biomarker-negative group. The median time from radical prostatectomy to entry into this study was 4.8 years (range, 3.1-7.9).

To be eligible for enrollment, patients had biochemically recurrent prostate cancer and underwent radical prostatectomy. In addition, patients had 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. Exclusion criteria included having radiographic evidence of metastatic disease via CT or bone scan, androgen deprivation therapy within 6 months, or prior androgen deprivation therapy for longer than 24 months.

Patients were to receive 300 mg of olaparib orally twice per day until baseline PSA doubled, clinical or radiographic progression, or unacceptable toxic effects.

The primary end point of this study was a confirmed 50% or higher decline in PSA. Key secondary end points included safety and tolerability of olaparib, and outcomes by homologous recombination repair alteration status, which included PSA progression-free survival, defined as time until a PSA increase of at least 25% above baseline or nadir and a minimum increase of 2.0 ng/mL.

Reference

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. Published online August 22, 2024. doi:10.1001/jamaoncol.2024.3074