Radiographic progression with nonrising PSA in metastatic castration-resistant prostate cancer: post hoc analysis of PREVAIL

Abstract

Background:Advanced prostate cancer is a phenotypically diverse disease that evolves through multiple clinical courses. PSA level is the most widely used parameter for disease monitoring, but it has well-recognized limitations. Unlike in clinical trials, in practice, clinicians may rely on PSA monitoring alone to determine disease status on therapy. This approach has not been adequately tested.Methods:Chemotherapy-naive asymptomatic or mildly symptomatic men (n=872) with metastatic castration-resistant prostate cancer (mCRPC) who were treated with the androgen receptor inhibitor enzalutamide in the PREVAIL study were analyzed post hoc for rising versus nonrising PSA (empirically defined as >1.05 vs ⩽1.05 times the PSA level from 3 months earlier) at the time of radiographic progression. Clinical characteristics and disease outcomes were compared between the rising and nonrising PSA groups.Results:Of 265 PREVAIL patients with radiographic progression and evaluable PSA levels on the enzalutamide arm, nearly one-quarter had a nonrising PSA. Median progression-free survival in this cohort was 8.3 months versus 11.1 months in the rising PSA cohort (hazard ratio 1.68; 95% confidence interval 1.26–2.23); overall survival was similar between the two groups, although less than half of patients in either group were still at risk at 24 months. Baseline clinical characteristics of the two groups were similar.Conclusions:Non-rising PSA at radiographic progression is a common phenomenon in mCRPC patients treated with enzalutamide. As restaging in advanced prostate cancer patients is often guided by increases in PSA levels, our results demonstrate that disease progression on enzalutamide can occur without rising PSA levels. Therefore, a disease monitoring strategy that includes imaging not entirely reliant on serial serum PSA measurement may more accurately identify disease progression.

Management of Patients with Advanced Prostate Cancer: The Report of the Advanced Prostate Cancer Consensus Conference APCCC 2017

“…The early identification of treatment failure in men with mCRPC on systemic therapy would help in sparing some patients futile treatment and potential toxicity as well as in reducing the costs of ineffective treatments and decreasing the time to initiation of a next-line, potentially effective treatment [110]. Recent data indicate that there are a substantial number of patients who have radiographic progression without PSA progression, including some patients with aggressive variant prostate cancer [111]. Imaging before treatment initiation and on-therapy may be important in predicting both benefit and more importantly nonbenefit of treatments.…”

Convergent evolution of p38/MAPK activation in hormone resistant prostate cancer mediates pro-survival, immune evasive, and metastatic phenotypes

“…Upon disease progression with enzalutamide or abiraterone treatment, most tumors remain AR dependent and have a rise in serum levels of prostate-specific antigen (PSA) (Bluemn et al, 2017; Bryce et al, 2017). Multiple mechanisms of AR signal restoration have been identified that directly impact the AR gene, including AR amplification, AR mutations, genomic structural rearrangements (Li et al, 2011b; Li et al, 2012; Liu et al, 2013; Ware et al, 2014), and alternative splicing events (Liu et al, 2014).…”

Monitoring Patients with Metastatic Hormone-Sensitive and Metastatic Castration-Resistant Prostate Cancer: A Multidisciplinary Consensus Document

“…Previous editions of the PCWG guidelines have highlighted the fact that PSA flares may occur during the early courses of chemotherapy, and it is recommended that discontinuing treatment on the basis of increasing PSA levels alone should be avoided during the first 12 weeks [26]. More recently, the role of PSA during treatment with ARTAs has also been revised on the basis of evidence showing that radiographic progression can occur in the absence of biochemical progression [19].…”

“…The need for imaging assessments should be determined on the basis of the findings of clinical/biochemical assessments, and carried out using the same methods as those used for the baseline assessment (preferably CT and BS). Biochemical and clinical progression usually precede radiological progression during ARTA treatment (median onset about 12 vs. 16-20 months), although radiographic progression in the absence of biochemical progression was recorded in 25% of the patients participating in the PREVAIL study [19]. There was below-threshold consensus (77%) for the inclusion of a predefined instrumental follow-up schedule (twice a year), but a consensus of about 90% for the recommendation that:…”