Elsevier

European Journal of Cancer

Volume 125, January 2020, Pages 153-163
European Journal of Cancer

Original Research
Clinical progression is associated with poor prognosis whatever the treatment line in metastatic castration resistant prostate cancer: The CATS international database

https://doi.org/10.1016/j.ejca.2019.10.030Get rights and content

Highlights

  • Metastatic castration-resistant prostate cancer (mCRPC) is treated by using several drugs.

  • Prognostic factors are useful to determine optimal treatment sequences in mCRPC.

  • Data were collected in 661 real-life patients over three successive treatment lines.

  • Post-hoc analysis showed that clinical progression was associated with poor outcomes.

  • Type of disease progression at the start of each line is a useful prognostic factor.

Abstract

Aim of the study

Our goal was to evaluate the impact of progression type (prostate-specific antigen [PSA] only, radiological or clinical) at initiation of first-, second- and third life-extending therapy (LET) on treatment outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients, by performing a post-hoc analysis using data from the CATS international registry.

Methods

The 669 consecutive mCRPC patients of the CATS registry were classified according to their type of progression at initiation of each LET: PSA only (PSA-p), radiological (±PSA) (Radio-p); or clinical (±PSA, ±radiological) progression (Clin-p). Overall survival (OS), the primary endpoint, was calculated from initiation of the first-, second- and third-LET to death for each sequence.

Results

Median OS was shorter in the Clin-p group compared with the PSA-p group (14-month difference in first line; around 7-month difference in second- and third line). Shorter progression-free survival (PFS) was also observed in Clin-p patients, whatever the treatment is. Clinical progression seemed to be associated with a shorter duration of therapy with androgen receptor-targeted therapy (ART) compared with taxanes.

Conclusions

Clinical progression at initiation of a LET is associated with poor outcomes including shorter PFS and OS as well as clinical and biological features of aggressive disease. Stratifying patients in clinical trials according to disease progression type may prevent selection bias and data heterogeneity. In daily practice, first signs of clinical progression may prompt physicians to consider starting a new LET, independently of PSA levels.

Introduction

Optimal management of metastatic castration-resistant prostate cancer (mCRPC) is still debated. Since docetaxel (DOC) approval in 2004 as first therapy able to extend overall survival (OS) in mCRPC [1], five other therapies (sipuleucel-T, cabazitaxel [CAB], abiraterone acetate [AA], enzalutamide [ENZA] and radium 223) have subsequently demonstrated an OS benefit in phase III clinical trials and were approved in this setting [2]. These phase III trials have been all conducted in parallel, with different inclusion and exclusion criteria (asymptomatic chemonaïve patients in some trials, no visceral metastases in others…) and different comparators (androgen deprivation therapy [ADT] ± prednisone with novel hormonal agents, sipuleucel-T and radium 223; mitoxantrone plus prednisone with chemotherapy or placebo).

The longest median OS in first-line mCRPC (median 34 months) has been observed in COU-AA-302 and PREVAIL phase III trials, which compared AA and ENZA in chemonaïve asymptomatic or mildly symptomatic mCRPC patients versus ADT alone [3,4]. In contrast, median OS with chemotherapy in first-line mCRPC was much shorter [1,5,6], but these trials included patients with more aggressive features, namely pain, which is a well-known poor prognostic factor [7,8]. Despite the lack of head-to-head comparisons, these novel androgen receptor-targeted therapies (ARTs) are recommended as first-line treatment by several international guidelines [2,9] and consensus conferences [10,11] for asymptomatic M1 patients until radiologic or symptomatic progression is observed, whereas chemotherapy is recommended for symptomatic patients or high-grade diseases. Of note, the NCCN guidelines recommend the use of ART solely for more severe M1 CRPC [12]. This discrepancy in recommendations highlights the need for an evidence-based and clinically driven definition of treatment sequences in mCRPC.

To identify prognostic factors, Armstrong et al. performed a multivariate analysis based on TAX327 data in mCRPC patients receiving DOC and identified several pre-treatment characteristics that could predict survival after chemotherapy [13,14]. These factors included types of disease progression, namely prostate-specific antigen (PSA) progression, bone scan progression and clinically measurable progression. In order to further validate these prognostic factors, additional analyses were carried out in patients enrolled in clinical trials, mainly in the post-DOC setting, taking into account only one line of treatment [[15], [16], [17], [18]]. In this context, we decided to conduct a post-hoc analysis of the CATS international registry [19] to evaluate the impact of progression type (PSA, radiological and clinical) at initiation of each LET on outcomes and treatment response in mCRPC. The CATS multicentre registry was designed to retrospectively collect medical data of a large cohort of consecutive mCRPC patients in a real-life setting. In addition, data were collected over three successive LETs (ART, DOC and CABA), in any order.

Section snippets

Data collection

Data were retrospectively collected from 669 consecutive patients with mCRPC treated with three consecutive LET (DOC→CABA→ART [DCA], n = 158, DOC→AA→CABA [DAC] n = 458, ART→DOC→CABA [ADC], n = 55), between November 2012 and October 2016, as previously published [19]. Confidentiality approval was obtained from the Commission Nationale de l’Informatique et des Libertés (CNIL), and the study was approved by the relevant ethics committees. All included patients were informed of this

Patient characteristics at initiation of first-LET

Among the 669 mCRPC patients included in the CATS study, type of progression was documented at initiation of first-, second- and third-LET in 661, 630 and 617 patients, respectively. Type of progression at initiation of each LET is provided in Fig. 1. Clinical progression was the most common progression type whatever the therapy line and its prevalence increased progressively with the number of lines (43.1%, 55.2% and 67.9% at first-, second- and third-LET initiation, respectively). Conversely,

Discussion

This retrospective analysis of 661 mCRPC patients treated by three LETs (DOC, CABA and one ART) provides strong evidence that clinical progression at initiation of each LET is associated with worse treatment outcomes. First, compared with patients with PSA progression only, patients with a clinical progression had a shorter OS whatever the line of treatment (9.7-month difference in first line; around 7-month difference in second- and third line) and a shorter PFS. In addition, the percentage of

Funding

This work was supported by the ARTIC association.

Conflict of interest statement

Nicolas Delanoy has received travel expenses for participation in medical meetings from Sanofi. Eleni Efstathiou has participated in studies and advisory boards for and received honoraria from Sanofi, Jannsen and Astellas and has participated in advisory boards for Tolmar, Takeda, Bayer and Tracon. Umberto Basso has received speaker fees from Bristol Meyer Squibb, Pfizer, Novartis, Pierre-Fabre and Sanofi and has participated in advisory boards for Janssen, Pfizer and Novartis. Alison Birtle

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      In the CARD study, most patients had pain progression at randomisation. Similar findings were reported in a large retrospective registry of 661 patients with metastatic castration-resistant prostate cancer treated in clinical practice.29 This situation possibly reflects recommendations of international guidelines and consensus conferences to continue androgen signalling-targeted inhibitors until unequivocal signs of progression (ie, imaging-based or clinical progression) before switching therapy.24,25

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