Travis Gerke

The time dependence in the performance of prognostic factors for cancer survival is typically incompletely understood, including in prostate cancer. We applied a “cumulative/dynamic” time-varying area under the curve (tAUC) for cumulative incidence of lethal prostate cancer (metastases/cancer-specific death). In two prospective prostate cancer patient cohorts followed for lethal outcomes after radical prostatectomy, genitourinary pathologists undertook a histopathologic review of tumor specimens to assign Gleason grade groups 1-5, a known strong short-term prognostic factor. Among 1490 patients, 144 lethal events occurred during 35 years of follow-up (median, 18). The 10-year risk of lethal disease was 2% (95% CI, 1-3) for grade group 2 and 21% (95% CI, 16-28) for grade group 5 cancers. By 25 years, risks were 5% (95% CI, 3-8) and 32% (95% CI, 26-41), respectively. Prediction accuracy was strongest over the first 10 years (tAUC 0.83 [95% CI, 0.79-0.86]) but remained informative for 25 years (tAUC 0.76 [95% CI, 0.70-0.81]), including among long-term metastasis-free survivors. Risk-based AUCs instead of hazard-based “incident/dynamic” AUCs allowed for interpretable characterization of prognostic accuracy over well-defined time periods. Lethal progression of high-grade prostate cancer occurred predominantly early, while that of lower grade tumors accumulated over decades after surgery.

Supplemental Table 2. SAEs per arm.

Supplemental Table 5. Treatment-Related AEs in Exploratory Arms.

Supplemental Table 4. Patient Demographics.

Supplemental Table 3. Reasons for not crossing over per arm.

Supplemental Table 6. Representativeness of Study Patients.

Supplemental Figure 1. PFS for primary arms.

Supplemental Figure 2. Outcomes for primary and exploratory arms.

Supplemental Table 1. Treatment Modifications.

Purpose: Deleterious germline/somatic homologous recombination repair mutations (HRRm) are present in ∼25% of patients with metastatic castration-resistant prostate cancer (mCRPC). Preclinically, poly(ADP-ribose) polymerase (PARP) inhibition demonstrated synergism with androgen receptor pathway (ARP)–targeted therapy. This trial evaluated the efficacy of ARP inhibitor versus PARP inhibitor versus their combination as first-line therapy in patients with mCRPC with HRRms. Patients and Methods: BRCAAway is a biomarker preselected, randomized, phase 2 trial. Patients with BRCA1/2 and/or ATM alterations were randomized 1:1:1 to Arm1: abiraterone (1,000 mg)/prednisone (5 mg BID) (Abi/pred), Arm2: olaparib (300 mg BID) (Ola), or Arm3: abiraterone/prednisone + olaparib (Abi/pred + Ola). Single-agent arms could cross over at progression. Exploratory Arm4 patients with other HRRms received olaparib alone. The primary endpoint was progression-free survival (PFS), and secondary endpoints were objective response, PSA response, and safety. Results: Sixty-one of 165 eligible patients had BRCA1/2 or ATM mutations: median age: 67 (IQR, 62–73) years. Mutations: BRCA1 n = 3, BRCA2 n = 46, ATM n = 11, and multiple n = 1; 33 germline and 28 somatic mutations. Median PFS [95% confidence interval (CI)]: Abi/pred, 8.6 months (m; 2.9, 17), Ola, 14 m (8.4, 20), and Abi/pred + Ola, 39 m [22, not reached (NR)]. There were no G4/5 adverse events; 8/19 patients on Abi/pred treatment crossed over to Ola, and 8/21 vice versa. Median PFS (95% CI) from crossover: Ola-after-Abi/pred, 8.3 m (5.5, 15) and Abi/pred-after-Ola, 7.2 m (2.8, NR). Median PFS (95% CI) from randomization: Ola-after-Abi/pred, 16 m (7.8, 25) and Abi/pred-after-Ola, 16 m (11, NR). Seventeen of 165 patients with other HRRms received olaparib: median PFS (95% CI): 5.5 m (2, 11). Conclusions: In patients with mCRPC with BRCA1/2 or ATM HRRm, Abi/pred + Ola was well tolerated and demonstrated longer PFS versus either agent alone or sequentially.