Olaparib Monotherapy Elicits Responses in HRR+ Prostate Cancer With High-Risk Biochemical Recurrence

Treatment with olaparib (Lynparza) monotherapy led to responses in patients with high-risk, biochemically recurrent (BCR) prostate cancer harboring homologous recombination repair (HRR) alterations, particularly among those with BRCA2 alterations, according to data from a phase 2 trial (NCT03047135) published in JAMA Oncology.

Findings showed that among all treated patients (n = 51), 26% (95% CI, 14%-40%) achieved a confirmed 50% or higher decline in prostate-specific antigen (PSA) from baseline (PSA50 response); however, no PSA50 responses were observed in patients in the HRR-negative group (n = 24), no PSA50 responses were recorded. In the HRR-positive group (n = 27), the PSA50 response rate was 48% (95% CI, 29%-68%).

Furthermore, all patients harboring BRCA2 alterations (n = 11) experienced a PSA50 response with a median duration of response (DOR) of 25.1 months (95% CI, 15.0-31.4). Two additional PSA50 responses were observed in 1 patient with a CHEK2 alteration and 1 patient with an ATM alteration.

“In this nonrandomized controlled trial, olaparib monotherapy led to high and durable PSA50 response rates in patients with BRCA2 alterations,” Catherine H. Marshall, MD, of Johns Hopkins University School of Medicine in Baltimore, Maryland, and co-authors wrote. “Olaparib warrants further study as a treatment strategy for some patients with BCR prostate cancer; [however, it] does not have sufficient activity in those without HRR alterations and should not be considered for those patients.”

Despite surgery or radiotherapy, approximately 40% of patients with localized prostate cancer will ultimately experience disease recurrence due to a rising PSA level in the absence of metastases, also known as BCR prostate cancer. Current therapeutic approaches for BCR prostate cancer include observation, salvage radiotherapy, androgen deprivation therapy (ADT), or enzalutamide (Xtandi) with or without ADT.

This phase 2 trial evaluated the efficacy and safety of olaparib monotherapy in patients with high-risk BCR prostate cancer in the absence of ADT. Investigators enrolled patients with a histologic diagnosis of prostate adenocarcinoma who underwent prior curative-intent radical prostatectomy and had prostate tissue available for correlative studies. Patients were enrolled from May 2017 to November 2022 across 4 trial sites in the United States, and they were eligible if they 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. Patients were ineligible for enrollment if they presented with radiographic evidence of metastatic disease based on conventional computed tomography or bone scan, received ADT within 6 months of enrollment, or received prior ADT for longer than 24 months.

Eligible patients enrolled onto this multicenter, single-arm, nonrandomized controlled trial received 300 mg of oral olaparib daily until a doubling of their baseline PSA level, clinical or radiographic progression, or unacceptable adverse effects (AEs).

The primary end point of the clinical trial was PSA50 response rate. Key secondary end points included safety and tolerability, time to PSA doubling from baseline, PSA progression-free survival (PFS), defined as time until a PSA increase of 25% or more above baseline or nadir and a minimum increase of 2.0 ng/mL.

Key exploratory end points of the investigation include outcomes by HRR alteration status. These positive biomarker results include germline or somatic ATM, BARD1, BRCA1/2, BRIP1, CDK12, CHEK1/2, FANCA, FANCE, PALB2, and RAD51B/C/D.

In the overall patient population (n = 51), the mean age of patients enrolled was 63.8 years (standard deviation [SD], 6.8), and a majority of patients were White (92%). The median PSA was 2.8 ng/mL (range, 1.0-37.6), the mean PSA doubling time was 2.92 months (SD, 1.5), and the median time from surgery to study start was 4.75 years (interquartile range, 3.1-7.9). Gleason grades included group 1 (2%), 2 (16%), 3 (37%), 4 (14%), and 5 (31%), and tumor stage at diagnosis ranged from T2 (31%), T3 (67%), and T4 (2%). Nodal stage at diagnosis was N0 (86%) and N1 (14%).

HRR alterations at baseline included BRCA2 (22%), ATM (12%), CHEK2 (12%), FANCA (4%), CDK12 (2%), and FANCE (2%). However, no patients had BRCA1 alterations, 8% had an unknown HRR status, and 39% of patients were HRR negative. Six percent of patients had ATM protein loss only, 2% had ATM genomic alteration only, 10% had both ATM protein loss and ATM genomic alteration, and 82% had neither ATM protein loss nor ATM genomic alteration. The biallelic HRR alteration rate was 23.5%. The mean gLOH score was 7.57 (SD, 3.1); however, data for 67% of patients were missing.

“The median overall PSA PFS in the cohort was 19.3 months [95% CI, 6.4–not reached (NR)]. The median time to PSA progression in the [HRR]-positive group was 22.1 months [95% CI, 6.4-NR] and in the [HRR]-negative group [the median PSA PFS] was 12.8 months [95% CI, 4.5-NR; HR for difference, 0.80; 95% CI, 0.33-1.97],” study authors stated of the secondary end points. “In the sensitivity analysis using restricted mean survival time [RMST] over 36 months, PSA PFS in the [HRR]-positive group vs the [HRR]-negative group was 19.3 months vs 8.5 months [P = .001]."

The median metastasis-free survival (MFS) was 32.9 months (95% CI, 24.6-56.7) in the overall population, 41.9 months (95% CI, 32.9-NR) in the HRR-positive group, and 16.9 months (95% CI, 10.9-NR) in the HRR-negative population. The RMST for MFS was 28.9 months over 3 years in the sensitivity analysis for patients in the HRR-positive group and 19.6 months in the HRR-negative group (P = .02).

The median time to next anticancer therapy was 15.4 months (95% CI, 11.1-24.6) in the overall group. However, there was a statistically significant longer time to next anticancer therapy in the HRR-positive group at 22.7 months (95% CI, 9.5-NR) vs 12.4 months (95% CI, 8.7-24.6) in the HRR-negative group (HR, 0.43; 95% CI, 0.21-0.90; P = .02).

“PSA50 responses were more frequent in [patients] with biallelic [12 of the 27 patients in the HRR-positive group] vs monoallelic HRR alterations,” study authors highlighted regarding exploratory end points. “Two of 11 [patients] with BRCA2 alterations and PSA50 responses did not have detectable biallelic alterations. The single [patient] with an ATM alteration and the single [patient] with a CHEK2 alteration who had PSA50 responses had monoallelic alterations with intact ATM protein expression.”

In 17 patients where gLOH score was evaluable, the median score was 8.1% (IQR, 5.9%-8.8%). Regarding PSA50 response rates among those with gLOH scores, there was no statistically significant difference among those with gLOH scores below the median vs above; there was no correlation between PSA response and gLOH score (R² = 0.04; P = .43; Spearman correlation coefficient, −0.21). Regarding PSA PFS by gLOH score, there was also no difference above or below the median (HR, 0.58; 95% CI, 0.13-2.61; P = .48), and there was no difference in MFS (HR, 0.28; 95% CI, 0.05-1.45; P = .13).

Additionally, 10% of participants had both ATM protein loss and ATM genomic alterations, 2% had an ATM genomic alteration only with preservation of ATM protein by immunohistochemistry, and 6% had ATM protein loss without detectable ATM genomic alterations.

Regarding safety, investigators wrote that the most common AEs were fatigue (63%), nausea (55%), and leukopenia (43%). No deaths due to AEs occurred during the trial. There were 2 serious AEs: anemia that was deemed related to the study drug and a cerebrovascular accident that was unrelated to olaparib.

Furthermore, 3 patients stopped therapy due to treatment-related AEs (anemia [n = 2] and leukopenia [n = 1]). One patient developed venous thromboembolism, which was deemed possibly related to study treatment. No new safety signals were reported with olaparib in this population.

“This study has several limitations, including a small sample size and lack of a control group,” study authors wrote. “We were not able to molecularly characterize all patients because insufficient nucleic acids were isolated from their prostatectomy specimens for downstream analysis in 4 patients.”

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.