Emerging Prognostic Groups Across the Spectrum of Metastatic Castration-Sensitive Prostate Cancer: Disease Outcomes and Genomics

PURPOSE/OBJECTIVE(S) Recent evidence has suggested metastatic cancer represents a disease spectrum rather than a binary state and metastasis-directed therapy (MDT) such as radiation may improve outcomes in some individuals with oligometastatic disease. Within metastatic castration-sensitive prostate cancer (mCSPC) several definitions categorize patients into low and high-volume disease. We assess these definitions, association with clinical outcome, and their mutational landscapes. MATERIALS/METHODS We retrospectively reviewed patients with biochemically recurrent (BCR) or mCSPC who had undergone somatic next-generation sequencing (n = 294). Patients were classified by low and high-volume disease per CHAARTED criteria, STAMPEDE criteria, oligo- or polymetastatic ≤ 3 vs > 3 and ≤ 5 vs > 5 metastases (mets). Kaplan-Meier survival curves were generated for time to development of castrate-resistant prostate cancer (tdCRPC) for each definition and compared using log rank test. Pearson's χ2 of Fischer's exact test determined differences in driver mutations. RESULTS Patients were classified with four different definitions as follows: CHAARTED low (53.1%) vs high volume (31.3%); STAMPEDE low (49.7%) vs high burden (35.4%); oligometastatic ≤ 3 (47.3%) vs > 3 (37.4%); and, ≤ 5 (54.1%) vs > 5 (30.6%). Median follow-up for the entire cohort was 52.3 months (mos). Median tdCRPC was not reached in patients with BCR; 85.4 vs 17.3 mos for CHAARTED low vs high, respectively; 99.3 vs 15.7 mos for STAMPEDE low vs high, respectively; 101.4 vs 15.7 mos for ≤ 3 vs > 3 mets respectively; and, 86.4 vs 15.4 mos for ≤ 5 vs > 5 mets respectively (P < 0.001 for all definitions). The frequency of mutations in WNT and cell cycle genes increased across the spectrum from BCR to highest volume of disease in all definitions. TP53 mutation frequency increased across the spectrum in the oligometastatic definitions (Table 1). CONCLUSION The spectrum of mCSPC disease biology is generally confirmed across four different definitions of disease burden for tdCRPC and genomics. For purposes of implementing MDT, a practical approach including an enumeration-centric definition integrated with genomics may be best. Future work will involve examining these various definitions and genomics in de novo and metachronous subsets.