McClure, Heather M.

AbstractBackgroundPARP (poly(ADP‐ribose) polymerase) inhibitors (PARPi) are now standard of care in metastatic castrate‐resistant prostate cancer (mCRPC) patients with select mutations in DNA damage repair (DDR) pathways, but patients with ATM‐ and BRCA2 mutations may respond differently to PARPi. We hypothesized that differences may also exist in response to taxanes, which may inform treatment sequencing decisions.MethodsmCRPC patients (N = 158) with deleterious ATM or BRCA2 mutations who received taxanes, PARPi, or both were retrospectively identified from 11 US academic centers. Demographic, treatment, and survival data were collected. Kaplan−Meier analyses were performed and Cox hazard ratios (HR) were calculated for progression‐free survival (PFS) as well as overall survival (OS), from time of first taxane or PARPi therapy.ResultsFifty‐eight patients with ATM mutations and 100 with BRCA2 mutations were identified. Fourty‐four (76%) patients with ATM mutations received taxane only or taxane before PARPi, while 14 (24%) received PARPi only or PARPi before taxane. Patients with ATM mutations had longer PFS when taxane was given first versus PARPi given first (HR: 0.74 [95% confidence interval [CI]: 0.37−1.50]; p = 0.40). Similarly, OS was longer in patients with ATM mutations who received taxane first (HR: 0.56 [CI: 0.20−1.54]; p = 0.26). Among patients with BRCA2 mutations, 51 (51%) received taxane first and 49 (49%) received PARPi first. In contrast, patients with BRCA2 mutations had longer PFS when PARPi was given first versus taxane given first (HR: 0.85 [CI: 0.54−1.35]; p = 0.49). Similarly, OS was longer in patients with BRCA2 mutations who received PARPi first (HR: 0.75 [CI: 0.41−1.37]; p = 0.35).ConclusionsOur retrospective data suggest differential response between ATM and BRCA2 mutated prostate cancers in terms of response to PARPi and to taxane chemotherapy. When considering the sequence of PARPi versus taxane chemotherapy for mCRPC with DDR mutations, ATM, and BRCA2 mutation status may be helpful in guiding choice of initial therapy.

481 Background: EV is an anti-Nectin-4 antibody-drug conjugate that has been approved by the US FDA for mUC progressing on platinum and PD1/L1 inhibitor therapy and in cisplatin-ineligible pts following prior therapy. However, prognostic and predictive biomarkers in the setting of EV therapy are unclear. We aimed to investigate baseline and early changes in commonly available clinical and laboratory tests that could help predict survival and toxicities in patients with mUC treated with EV. Methods: Data from patients with mUC who were treated with EV at Dana Farber Cancer Institute between 2017 and 2021 were reviewed retrospectively. We assessed the association of demographic (age, sex), clinical (ECOG-performance status [PS], sites of metastasis) and laboratory variables (hemoglobin, RDW, neutrophil count, lymphocyte count, neutrophil-to-lymphocyte ratio, platelet count and serum albumin) at baseline as well as after 4-7 weeks of treatment with Overall Survival (OS) by constructing univariate and multivariable Cox proportional-hazards models. Any variables significantly associated with OS at the univariate level (using an alpha-level of 0.1 to determine statistical significance) were then entered into the multivariable model. Predictors were eliminated from the final multivariable models by a backward selection process, retaining only those with a p-value of ≤ 0.05. Results: A total of 49 patients who received EV were included in the analysis. The median age was 72 years (range 48-88) and 36 (73.5%) were male. The median OS was 13.3 months (range: 2.7-38.7) and grade 3-4 toxicities were seen in 11 pts (22.4%). In the final multivariable models, lower serum albumin at 4-7 weeks (HR = 0.18; 95% CI = 0.05-0.71; p = 0.015), and baseline ECOG-PS of 1 vs. 0 (HR = 2.56; 95% CI = 1.05-6.21; p = 0.038) were significantly associated with worse OS (Table). Patients with higher serum albumin levels at 4-7 weeks also had significantly lower odds of experiencing grade 3-4 adverse events on EV (OR = 0.05; 95% CI = 0.002-0.52; p = 0.02). Conclusions: Lower serum albumin appeared to predict worse survival and severe toxicities in mUC pts receiving EV. This information may guide therapy and assist in the prevention of toxicities. Additionally, ECOG-PS was prognostic while the location of metastatic disease was not prognostic in the setting of EV.[Table: see text]

5040 Background: PARPi have shown promise in mCRPC pts with mutations in DNA repair, but ATM- and BRCA2-altered pts may respond differently to PARPi. We hypothesized that differences may also exist for taxane therapy, aiding in treatment sequencing decisions. Methods: mCRPC pts (N = 137) with deleterious ATM or BRCA2 mutations who received taxanes, PARPi, or both were identified from 8 US academic centers. Demographic, treatment, and survival data were collected. Kaplan-Meier analyses were performed for time-to-treatment-discontinuation (TTD), as well as overall survival (OS), from time of first taxane or PARPi therapy. Cox hazard ratio (HR) regression analyses were performed, adjusting for Gleason sum (≤7 vs. 8-10). For OS, receipt of subsequent therapies following first taxane or PARPi was also included as a covariate. Results: 50 ATM- and 87 BRCA2-mutated pts were identified. 40/50 (80%) of ATM-mutated pts received taxane only or taxane prior to PARPi, while 10/50 (20%) received PARPi only or PARPi prior to taxane. ATM-mutated pts showed a trend towards longer TTD when taxane was given first vs PARPi given first (P = 0.08, adjusted HR for taxane treatment 0.50 [95% CI: 0.24–1.08]). Considering all pts who received taxane first, ATM-mutated pts had longer TTD than BRCA2-mutated pts who received taxane first ( P= 0.04, adjusted HR for ATM 0.61 [CI: 0.37–0.99]). Among ATM-mutated pts, OS was longer in those receiving taxane first ( P= 0.06, adjusted HR for taxane treatment 0.33 [CI: 0.10–1.05]). Among BRCA2-mutated pts, 43/87 (49%) received taxane first and 44/87 (51%) received PARPi first. BRCA2-mutated pts had longer TTD when PARPi was given first vs taxane given first ( P< 0.0001, adjusted HR for PARPi treatment 0.32 [CI: 0.19–0.56]). Considering all pts who received PARPi first, BRCA2-mutated pts also had longer TTD than ATM-mutated pts who received PARPi first ( P= 0.0031, adjusted HR for BRCA2 0.29 [CI: 0.12–0.66]). There was no significant OS difference in BRCA2-mutated pts regarding which treatment was given first ( P= 0.63, adjusted HR for PARPi treatment 1.18 [CI: 0.59–2.35]). Conclusions: Our data in ATM- and BRCA2-mutated mCRPC pts suggests a trend towards improved clinical outcomes when taxanes are used prior to PARPi in ATM-mutated pts, while the reverse sequence appears to be better for BRCA2-mutated pts.[Table: see text]