Randomized phase II study of olaparib (Ola) maintenance following cabazitaxelcarboplatin induction chemotherapy (CabCarb) in men with aggressive variant prostate cancer (AVPC).

196 Background: An aggressive subset of prostate cancers (AVPC) respond poorly to androgen signaling inhibitors, have limited therapeutic options and a dismal prognosis. Preclinical models of AVPC display functional alterations in DNA damage response (DDR) pathways linked to platinum and PARP inhibitor (PARPi) sensitivity. We hypothesized that PARPi (ola) maintenance following CabCarb would improve the progression free survival (PFS) of men with AVPC. We performed a tissue-rich randomized trial for men with AVPC to address this hypothesis and unravel the heterogeneity of AVPC by linking genomic and transcriptomic analyses with clinical outcomes. Methods: In a single-institution study, men with CRPC meeting ≥ 1 of 9 AVPC criteria and ECOG performance status (PS) of 0-2 received 6 cycles of Cab 20-25mg/m2 and Carbo (AUC 3-4). Men completing 6 cycles without progressive disease (PD) were randomized 2:1 to Ola 300mg BID vs. observation (Obs). The primary endpoint is to estimate PFS in those randomized and we aimed to detect a difference of 3.9 vs. 7.8 months. Subgroup comparisons between patients who had PD prior to randomization (platinum-resistant) vs. those randomized (platinum sensitive) were made with chi-square tests for categorical baseline characteristics, and Kruskal-Wallis test for continuous measures. Results: 96 patients started CabCarb. Their median age was 67 years (43-86), most were white/non-Hispanic (74%), had an ECOG score of 0 (64%), bone metastases (79%), and no prior docetaxel therapy (59%). Of the 96, 7 (7.3%) went off study for reasons unrelated to PD and 36 (37.5%) had PD prior to randomization. Patients with PD prior to randomization were more likely at baseline to have received prior docetaxel (59% vs. 29%; p=0.004), have bone metastases (92% vs. 71%; p=0.03), have lower hemoglobin (11.4 vs. 12. 4; p=0.02), higher LDH (359 vs. 260; p=0.01), lower albumin (4.0 vs. 4.2; p=0.04), and higher AlkPhos (181.5 vs. 98.5; p=0.01) compared to patients who went on to randomization. With a median follow up time of 38.9 months post randomization, the median PFS was 2.3 months (95% confidence interval: 1.3, 4.6 months) for Observation and 4.9 (3.5, 6.3) months with Olaparib (p=0.12). The median OS was 16.2 (6.8, 26.4) for observation and 15.3 (10.2, 28.4) months with Olaparib (p=0.56). Conclusions: These data highlight the heterogeneity within the AVPC subset. Ongoing molecular analyses of sequential liquid and tumor tissue will illuminate the underpinnings of this heterogeneity and identify targets for additional combinatorial strategies. Clinical trial information: NCT03263650 .