Outcomes of treatment choices in poor prognosis prostate cancer: not against all odds

‘What is the best choice of first-line treatment in men with poor prognosis metastatic castration-resistant prostate cancer (mCRPC)?’ Up until today, this important topic under debate daily practice. Although guidelines advocate use taxanes as first CRPC1Gillessen S. Attard G. Beer T.M. et al.Management patients advanced cancer: report consensus conference 2019.Eur Urol. 2020; 77: 508-547Abstract Full Text PDF PubMed Scopus (194) Google Scholar and pivotal studies androgen receptor pathway inhibitors (ARPIs), including abiraterone enzalutamide, typically enrolled a relatively good prognosis,2Beer Armstrong A.J. Rathkopf D.E. al.Enzalutamide before chemotherapy.N Engl J Med. 2014; 371: 424-433Crossref (1631) Scholar,3Ryan C.J. Smith M.R. Fizazi K. al.Abiraterone acetate plus prednisone versus placebo chemotherapy-naive (COU-AA-302): final overall survival analysis randomised, double-blind, placebo-controlled phase 3 study.Lancet Oncol. 2015; 16: 152-160Abstract (900) ARPI has increased over past years irrespective prognostic features.4Oh W.K. Cheng W.Y. Miao R. al.Real-world outcomes receiving second-line chemotherapy an alternative receptor-targeted agent (ARTA) following early progression on ARTA US community oncology setting.Urol 2018; 36: 500.e1-500.e9Google Scholar,5de Wit Freedland Oudard evidence (RWE) for (pts) (mCRPC) treated cabazitaxel (CBZ): Comparison randomized clinical study CARD.Ann 31: S518Abstract In issue Annals Oncology, Annala al. outcome II trial (abiraterone or enzalutamide).6Annala M. Fu Bacon J.V.W. al.Cabazitaxel enzalutamide multicentre, open-label, trial.Ann 2021; 32: 896-905Abstract (16) Unfortunately, recruitment had to be halted at 95 targeted 120 due slow accrual. Twenty-five (26%) been docetaxel castrate-naïve PC (mCNPC) setting 26 (27%) prior mCRPC. Inevitably, both modest sample size well heterogeneity treatments affected reported outcomes. Nonetheless, data here may relevant guiding decisions. CRPC was defined presence liver metastases, and/or development castration-resistance within 12 months surgical chemical castration disease, least four six factors: lactate dehydrogenase > upper limit normal (ULN), Eastern Cooperative Oncology Group (ECOG) performance status 2, visceral serum albumin ≤4 g/dl, alkaline phosphatase ULN, <36 from start initial deprivation therapy enrolment. Clinical benefit rate (CBR) primary composite endpoint (defined specific antigen decline ≥50% baseline, measurable radiographic response any duration, stable disease ≥12 weeks absence other indicators progression). CBR significantly better (80% 62%, P = 0.039, adjusted docetaxel). This almost exclusively based 19% difference beyond weeks. Progression-free nearly twice long (5.3 2.8 months, HR 0.87, 0.52) median (OS) favored (37.0 15.5 0.58, 0.073), but view these notable differences did not reach statistical significance. With caution small numbers, by docetaxel. Also, who crossed opposite therapy, there larger than vice versa. meet boundaries, findings considered clinically relevant. Together recent CARD which demonstrated reduced risk death 36% compared second – even third line 7de de Bono J. Sternberg C.N. cancer.N 2019; 381: 2506-2518Crossref (246) results evidently show need smart timing cabazitaxel, especially are rapidly failing therapies those unfavorable characteristics. Cabazitaxel often perceived drug last resort. Due concerns about toxicity, many patients, features, back-to-back instead cabazitaxel,5de though lack efficacy consecutive ARPI.4Oh Scholar,7de Scholar, 8Attard Borre Gurney H. alone combination rising prostate-specific during treatment.J Clin 2639-2646Crossref (92) 9Khalaf D.J. Taavitsainen al.Optimal sequencing crossover trial.Lancet 20: 1730-1739Abstract (145) 10Buck S.A.J. Koolen S.L.W. Mathijssen R.H.J. al.Cross-resistance sequence cancer.Drug Resist Updat. 56: 100761Crossref (11) Not losing window opportunity, great importance.11Delanoy N. Robbrecht D. Eisenberger al.Pain initiation (mCRPC): post hoc PROSELICA study.Cancers (Basel). 13: 1284Crossref (1) Scholar,12Robbrecht D.G. Delanoy Tannock I.F. al.Impact baseline on-treatment events three large trials.Eur Cancer. 125: 142-152Abstract (6) 85 were eligible only 55 (58%) actually received treatment, mostly frailty after previous treatment.6Annala study, 22% progressed arm subsequently palliative radiotherapy no subsequent all, suggesting >50% have missed opportunity more effective treatment.7de Importantly, it found that frequencies grade greater adverse quite similar (25 mg/m2 granulocyte colony-stimulating factor prophylaxis) ARPI.7de A lower dose 20 yet another option shown non-inferior 25 respect tolerated.13Eisenberger Hardy-Bessard A.C. Kim C.S. al.Phase III comparing (20 mg/m(2)) currently approved postdocetaxel cancer-PROSELICA.J 2017; 35: 3198-3206Crossref (171) Scholar,14Oudard Sengelov L. trial-FIRSTANA.J 3189-3197Crossref (176) real-world retrospective CARD-like population 452 showed despite poorer ECOG status, aggressive duration comparable what observed study.5de Better tolerability lead improved adherence chance therapy. To further support clinicians their decisions, predictive biomarkers needed. carried out translational research explore associations between endpoints ctDNA (circulating tumor DNA) dynamics genomic alterations ctDNA. 80% fractions >2% confirming association higher levels features previously same authors.15Annala Vandekerkhove Khalaf al.Circulating DNA genomics correlate resistance cancer.Cancer Discov. 8: 444-457Crossref The investigators level above cohort median) strongest survival. clear whether stronger one two arms. identified Robust conclusions hampered size. ctDNA-based evaluations do hold promising potential identification markers trial, presented preference mCRPC.6Annala ARPIs very contribution armamentarium cancer, ‘not against all odds’.