Prostate-specific antigen flare induced by cabazitaxel-based chemotherapy in patients with metastatic castration-resistant prostate cancer

doi:10.1016/j.ejca.2014.03.015

European Journal of Cancer

Volume 50, Issue 9, June 2014, Pages 1602-1609

https://doi.org/10.1016/j.ejca.2014.03.015 Get rights and content

Abstract

Background

A prostate-specific antigen (PSA) flare occurs in about 15% of metastatic castration-resistant prostate cancer (mCRPC) patients receiving docetaxel. This flare has no standard definition. Its impact on treatment efficacy is unclear. We sought to evaluate the incidence and characteristics of PSA flare on cabazitaxel, and its impact on survival.

Methods

Multicentre retrospective review of consecutive patients treated with cabazitaxel second-line chemotherapy for mCRPC. Collection of baseline characteristics, disease history and PSA levels before and during cabazitaxel therapy. Overall survival (OS) and radiological/clinical progression-free survival (PFS) for patient groups corresponding to different definitions of PSA flare estimated by the Kaplan–Meier method and compared using the log-rank test.

Results

Overall, 125 patients were included. Median PFS and OS were 6.5 and 13.3 months, respectively. Depending upon the definition used, flare incidence ranged from 8.3% to 30.6%. The flare lasted <2.6 months. A PSA flare followed by a ⩾50% decrease was associated with a median PFS and OS of 11.2 and 25.2 months, respectively. Median PFS and OS for a ⩾30% rather than ⩾50% decrease were 10.4 and 16.5 months. These outcomes were not significantly different from those in patients with immediate PSA decreases of ⩾50% or ⩾30% from baseline, but were significantly better than in patients experiencing no PSA decrease (p = 0.006 and 0.015, respectively, for OS).

Conclusion

The PSA response to cabazitaxel, with or without initial flare, was associated with a strong survival benefit. The taxane-induced flare during the first 12 weeks of therapy can be ignored when evaluating PSA response.

Introduction

Over the last 10 years or so, major advances have been made in the treatment of metastatic castration-resistant prostate cancer (mCRPC) [1]. Cabazitaxel is a newly available taxane which has shown survival benefit in mCRPC patients progressing during or after docetaxel therapy [2], [3], [4], [5], [6]. As for any other drug, clinicians need to learn to use the drug properly to optimise patient outcomes. A specific issue that needs to be addressed with taxanes is the early PSA flare. This is an isolated PSA rise that occurs after initiation of taxane therapy. It is uncertain whether it should lead to treatment discontinuation or not.

An early PSA flare (aka ‘PSA surge’) followed by a decrease in PSA was first reported in 2004 [7] and has been documented in up to 20% of mCRPC patients treated with first-line docetaxel chemotherapy but its impact on treatment outcome and patient management is unclear. Four retrospective studies have concluded that such a flare is not associated with adverse outcomes and can therefore be disregarded ([8], [9], [10], [11], see [12] for review). However, these studies involved small patient numbers and did not use a standard definition for the PSA flare. Any initial rise, whether relative or absolute, in PSA is considered to signal a flare. On the other hand, there is no consensus on the extent of the subsequent PSA decline for the phenomenon to be a flare. It may be a ⩾50% decline of the peak or baseline PSA value, a stable PSA of no given threshold, or even an undefined PSA response [8], [9], [10], [11]. In addition, available studies do not indicate clearly whether the observed lack of impact of the flare on treatment outcomes applies to just docetaxel, to just first-line taxane chemotherapy, or can be generalised to various chemotherapy regimens.

The aim of our study was to establish the incidence and characteristics of the PSA flare in mCRPC patients treated with second-line cabazitaxel after progression during or after docetaxel therapy. We used different definitions of PSA flare to assess the impact of flare on overall survival (OS) and on clinical or radiological progression-free survival (PFS). The underlying purpose was to determine whether the flare should or should not prompt treatment discontinuation in clinical practice.

Section snippets

Patients and methods

Data on consecutive mCRPC patients treated with cabazitaxel for progression during or after docetaxel were collected retrospectively in nine centres (eight in France and one in Turkey) using an electronic case report form. Patients had received cabazitaxel between January 2007 and May 2012 either in the TROPIC phase III trial (NCT00417079) or in the cabazitaxel compassionate use programme implemented before the availability of the drug on the market. Cabazitaxel was administered as recommended,

Population characteristics and outcomes of cabazitaxel therapy

At the time of data collection, 170 mCRPC patients had been treated with cabazitaxel in the participating centres. Twelve patients were excluded because they had received only one cycle of cabazitaxel and 33 patients because of insufficient follow-up. This left 125 patients for inclusion in the present study (46 from the TROPIC trial; 79 from the compassionate use programme). Their characteristics, including data on prior treatments, are given in Table 1. Median age at the first cycle of

Discussion

Our study analysed the early PSA flare occurring on second-line chemotherapy of mCRPC patients with the recently available taxane, cabazitaxel. Two-thirds of the 125 patients had been treated outside a clinical trial in a real-life setting. The incidence of a PSA flare ranged from 8.3% to 30.6% depending upon the definition used for flare and was roughly similar to that recorded for first-line docetaxel chemotherapy (11–18%) [8], [9], [10], [11]. The time to peak of the cabazitaxel-induced PSA

Conclusions

In conclusion, the initial PSA flare during second-line cabazitaxel therapy was not associated with a worse outcome if followed by a PSA decrease of ⩾30% or ⩾50% from baseline. This finding provides additional support to the PCWG2 recommendation that an early PSA rise (prior to 12 weeks) on administration of a cytotoxic agent should be ignored in evaluating PSA response and should not be interpreted by clinicians as immediate disease progression necessitating treatment discontinuation [13].

Conflict of interest statement

AA: Honoraria: Entity: Sanofi-Aventis, Relationship: Myself.
AF: Honoraria: Entity: Sanofi-Aventis, Astellas, Janssen, Ferring, Relationship: Myself.
MO: Consultant or Advisory Role, Entity: Sanofi-Aventis, Janssen, Astellas, Relationship: Myself, Compensation: Compensated.
FM: Consultant or Advisory Role, Entity: Sanofi-Aventis, GlaxoSmithKline, Bristol Myers Squibb, Celgene, Boston Scientific, Relationship: Myself, Compensation: Compensated.
GG: Consultant or Advisory Role, Entity:

Acknowledgements

Guillaume Moriceau, resident oncologist in Saint-Etienne, and all staff who helped collect data in the participating centers.

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Sequencing impact and prognostic factors in metastatic castration-resistant prostate cancer patients treated with cabazitaxel: A systematic review and meta-analysis
2023, Urologic Oncology: Seminars and Original Investigations
Citation Excerpt :
Furthermore, Fujiwara et al. demonstrated that more than 30% decrease of PSA after 3 cycles was associated with a better OS (HR 2.58, 95% CI: 1.19–6.06) [35]. Angelergues et al. reported that PSA flare after cabazitaxel, defined as any rise in PSA followed by 30% or 50% decrease within 3 months, had no statistically significant association with PFS or OS [34]. In this systematic review and meta-analysis, we found that sequential therapy with cabazitaxel was associated with an improved OS compared to that with other agents in post-docetaxel mCRPC patients.
Cabazitaxel is an effective treatment of post-docetaxel metastatic castration-resistant prostate cancer (mCRPC). We aimed to assess the sequencing impact and identify prognostic factors of oncologic outcomes in mCRPC patients treated with cabazitaxel.
PUBMED, Web of Science, and Scopus databases were searched for articles published before January 2022 according to the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) statement. Studies were deemed eligible if they investigated pretreatment clinical or hematological prognostic factors of overall survival (OS) in mCRPC patients with progression after docetaxel treated with available treatments including cabazitaxel.
Overall, 22 studies were eligible for the meta-analysis. In mCRPC patients treated with docetaxel, subsequent treatment with cabazitaxel was associated with better OS compared to that without cabazitaxel (pooled hazard ratio [HR]: 0.70, 95% confidence interval [CI]: 0.56–0.89). Among the patients treated with cabazitaxel, several pretreatment clinical features and hematologic biomarkers were associated with worse OS as follows: poor performance status (PS) (pooled HR: 1.92, 95% CI: 1.33–2.77), presence of visceral metastasis (pooled HR: 2.13, 95% CI: 1.62–2.81), symptomatic disease (pooled HR: 1.47, 95% CI: 1.25–1.73), high PSA (pooled HR: 1.76, 95% CI: 1.27–2.44), high alkaline phosphatase (ALP) (pooled HR: 1.45, 95% CI: 1.28–1.65), high lactate dehydrogenase (LDH) (pooled HR: 1.54, 95% CI: 1.00–2.38), high c-reactive protein (CRP) (pooled HR: 4.40, 95% CI: 1.52–12.72), low albumin (pooled HR:1.09, 95% CI: 1.05–1.12) and low hemoglobin (pooled HR:1.55, 95% CI: 1.20–1.99).
Sequential therapy with cabazitaxel significantly improves OS in post-docetaxel mCRPC patients. In mCRPC patients treated with cabazitaxel, patients with poor PS, visceral metastasis, and symptomatic disease were associated with worse OS. Further, pretreatment high PSA, ALP, LDH or CRP as well as low hemoglobin or albumin, were blood-based prognostic factors for OS. These findings might help guide the clinical decision-making for the use of cabazitaxel and prognostication of its OS benefit.
Prostate-specific Antigen Progression in Enzalutamide-treated Men with Nonmetastatic Castration-resistant Prostate Cancer: Any Rise in Prostate-specific Antigen May Require Closer Monitoring
2020, European Urology
There is no universally accepted definition for prostate-specific antigen (PSA) progression. However, changes in PSA in patients with castration-resistant prostate cancer (CRPC) are used to inform treatment decisions.
To determine whether the Prostate Cancer Working Group 2 (PCWG2) definition of PSA progression is adequate to predict radiographic or clinical progression in enzalutamide-treated men with nonmetastatic CRPC (nmCRPC).
A post hoc, retrospective analysis of men with nmCRPC from PROSPER (NCT02003924) was performed.
Continued androgen deprivation therapy; patients randomized 2:1 to enzalutamide 160 mg/d or placebo.
Metastasis-free survival (MFS) in men with and without PSA progression, defined by PCWG2, and PSA at the time of radiographic progression were assessed.
As of June 28, 2017, in enzalutamide-treated patients, the risk of metastasis or death was increased significantly in those with PSA progression versus those without (hazard ratio [HR] 3.99; 95% confidence interval [CI], 2.95–5.41; p < 0.0001). Median MFS was not reached (NR; 95% CI, NR–NR) in patients without PSA progression and was 22.6 mo (95% CI, 21.9–29.0) in those with PSA progression. In placebo-treated patients, PSA progression was not significantly associated with MFS (HR 1.72; 95% CI, 0.86–3.45; p = 0.1). Median MFS was NR (95% CI, 25.6–NR) in patients without PSA progression and 18.3 mo (95% CI, 14.9–19.4) in those with PSA progression. The median PSA increase from nadir at the time of radiographic progression was 1.4 ng/mL in enzalutamide-treated men and 25.6 ng/mL for the placebo arm.
In men with nmCRPC and rapidly rising PSA, radiographic progression often occurred without PCWG2-defined PSA progression, suggesting that any increase in PSA may warrant closer monitoring. While PCWG2-defined PSA progression was associated with radiographic progression in enzalutamide-treated men, our findings argue for prospective re-evaluation of this threshold.
In this report, we looked at changes in prostate-specific antigen (PSA) in enzalutamide-treated men with nonmetastatic castration-resistant prostate cancer who no longer respond to testosterone-lowering treatment. We found that even very small changes in PSA while on treatment could be an early indication of disease progression and should trigger closer monitoring.
Early Post-treatment Prostate-specific Antigen at 4 Weeks and Abiraterone and Enzalutamide Treatment for Advanced Prostate Cancer: An International Collaborative Analysis
2020, European Urology Oncology
Citation Excerpt :
In this study, PSA declines were associated with taxane responses, and decreased androgen receptor nuclear localisation and increased microtubule bundling in circulating tumour cells [16]. Nevertheless, PCWG3 criteria have discouraged treatment decisions based on early PSA changes, since flare reactions within the first 12 wk of treatment have been described in approximately a third of patients treated with docetaxel and cabazitaxel [3,10,11]. In our previously reported single-centre retrospective analysis, on a cohort of 274 mCRPC patients treated at the Royal Marsden Hospital, we have reported that a 30% PSA decline at 4 wk was associated with longer OS, significantly correlating with PSA falls at 12 wk [12].
Declines in prostate-specific antigen (PSA) levels at 12 wk are used to evaluate treatment response in metastatic castration-resistant prostate cancer (mCRPC). PSA fall by ≥30% at 4 wk (PSA4w30) has been reported to be associated with better outcome in a single-centre cohort study.
To evaluate clinical relevance of early PSA decline in mCRPC patients treated with next-generation hormonal treatments (NGHTs) such as abiraterone and enzalutamide.
This was a retrospective multicentre analysis. Eligible patients received NGHT for mCRPC between 6 January 2006 and 31 December 2017 in 13 cancer centres worldwide, and had PSA levels assessed at baseline and at 4 and/or 12 wk after treatment. PSA response was defined as a ≥30% decline (progression as a ≥25% increase) from baseline.
Association with overall survival (OS) was analysed using landmark multivariable Cox regression adjusting for previous chemotherapy, including cancer centre as a shared frailty term.
We identified 1358 mCRPC patients treated with first-line NGHT (1133 had PSA available at 4 wk, and 948 at both 4 and 12 wk). Overall, 583 (52%) had a PSA4w30; it was associated with longer OS (median: 23; 95% confidence interval [CI]: 21–25) compared with no change (median: 17; 95% CI: 15–18) and progression (median: 13; 95% CI: 10–15). A PSA12w30 was associated with lower mortality (median OS 22 vs 14; hazard ratio = 0.57; 95% CI = 0.48–0.67; p < 0.001). PSA4w30 strongly correlated with PSA12w30 (ρ = 0.91; 95% CI = 0.90–0.92; p < 0.001). In total, 432/494 (87%) with a PSA4w30 achieved a PSA12w30. Overall, 11/152 (7%) patients progressing at 4 wk had a PSA12w30 (1% of the overall population).
PSA changes in the first 4 wk of NGHT therapies are strongly associated with clinical outcome from mCRPC and can help guide early treatment switch decisions.
Prostate-specific antigen changes at 4 wk after abiraterone/enzalutamide treatment are important to determine patients’ outcome and should be taken into consideration in clinical practice.
Results of the FLAC European Database of Metastatic Castration-Resistant Prostate Cancer Patients Treated With Docetaxel, Cabazitaxel, and Androgen Receptor–Targeted Agents
2018, Clinical Genitourinary Cancer
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Imaging (bone scan with or without computed tomographic scan for patients with measurable disease) had been performed every 2 or 3 therapy cycles at the physician’s discretion. A proportion of our cohort of patients had been included in a previous study, which examined the prostate-specific antigen (PSA) flare induced by CABA.7 Patients were grouped according to the sequence of treatments received: group 1 had been treated with the sequence androgen-deprivation therapy (ADT) → DOC → CABA only; group 2 had received ADT → DOC → ART → CABA; and group 3 had received ADT → DOC → CABA → ART.
Several agents have demonstrated an overall survival (OS) benefit in patients with metastatic castration-resistant prostate cancer (mCRPC); however, the optimal sequencing of these therapies is unknown as a result of a lack of prospective randomized controlled trials. This retrospective study aimed to identify clinical factors influencing outcomes and to determine optimal treatment sequencing in patients with mCRPC treated with cabazitaxel (CABA) and/or androgen receptor–targeted agents (ART) after androgen-deprivation therapy (ADT) and docetaxel (DOC).
Records of 574 consecutive patients treated (2012−2016) at 44 centers in 6 countries were retrospectively examined.
A total of 267 patients received ADT → DOC → CABA (group 1), 183 patients ADT → DOC → ART → CABA (group 2), and 124 patients ADT → DOC → CABA → ART (group 3), with respective median OS from diagnosis of mCRPC of 38.3, 44.45, and 53.9 months (P = .012 for group 3 vs. group 1). Multivariate analysis showed response to first ADT ≤ 12 months, Gleason score of 8 to 10, clinical progression, and high prostate-specific antigen levels at mCRPC diagnosis were associated with worse OS. Prior receipt of ART did not influence activity of CABA.
OS appeared to increase with the number of life-extending therapies, with a sequence including DOC, CABA, and an ART providing the greatest OS benefit.
Early abiraterone acetate treatment is beneficial in Japanese castration-resistant prostate cancer after failure of primary combined androgen blockade
2018, Prostate International
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The latter phenomenon is followed by a decrease in PSA levels shortly after initial treatment with agents such as LHRH analogs, AA, and taxane. Previous reports indicated that this phenomenon was observed in 5–30% of patients receiving an LHRH analog and in 8–20% of patients receiving taxane chemotherapy.18–22 However, its predictive value of prognosis or occurrence of adverse events is unclear.
Development of novel agents targeting the androgen axis has led to improved overall survival in castration-resistant prostate cancer (CRPC). This study aimed to investigate the optimal timing of treatment with one such agent, abiraterone acetate (AA), in Japanese patients.
Between July 2014 and February 2016, 106 CRPC patients were administered AA in Nagoya City University Hospital, Nagoya, Japan and in four affiliated hospitals following failure of primary combined androgen blockade (CAB). Of these, records of 69 patients treated before chemotherapy were retrospectively analyzed. Patients were divided into two AA treatment groups: (1) first- or second-line after diagnosis of CRPC, designated the Early Group, and (2) third-line onwards, designated the Deferred Group. Prostate-specific antigen (PSA) response rate, ≥ 50% PSA decline rate with treatment, progression-free survival (PFS), and overall survival (OS) were compared between the two groups. National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 was used to classify adverse events.
In 24 patients in the Early Group and 45 patients in the Deferred Group, no significant differences in baseline parameters were observed between groups. PSA response rate, ≥ 50% PSA decline rate and PFS (but not OS) were significantly better in the Early Group than in the Deferred Group. Serum aspartate aminotransferase/alanine aminotransferase elevations were the most common Grade 3 treatment-related toxicities, and were clinically manageable. In subgroup analyses of the Early Group, comparison of first-line AA with second-line AA after flutamide treatment showed no changes in PSA response rate, PFS, or OS.
This study suggests improved favorable outcomes of first- or second-line AA treatment in Japanese chemotherapy-naïve CRPC patients after failed CAB; statistical confirmation of such improvement was evident for PFS, but not OS. In addition, early AA treatment exhibited an acceptable safety profile.
The Contemporary Use of Radium-223 in Metastatic Castration-resistant Prostate Cancer
2018, Clinical Genitourinary Cancer
Radium-223 dichloride (radium-223) was approved for the treatment of patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases in the United States and Europe in 2013. This followed a reported overall survival benefit for patients treated with radium-223 and best standard of care (BSoC) when compared with placebo and BSoC in the ALpharadin in SYMptomatic Prostate CAncer (ALSYMPCA) trial. At that time, docetaxel was the standard first-line choice for patients with metastatic CRPC (mCRPC). Since then, the treatment landscape has changed dramatically with new hormonal agents (abiraterone and enzalutamide) considered to be the first-line choice for many patients. The optimal patient profile for radium-223 in the modern setting, and its best use either in sequence or in combination with other approved agents are unclear, with few definitive guidelines available. This article reports on the views of a group of urologists and medical oncologists experienced in treating patients with mCRPC with radium-223 in routine clinical practice. The aim is to provide an overview of the current use of radium-223 in the treatment of patients with mCRPC, and to discuss best practices for patient selection and on-treatment monitoring. Where agreement was reached, guidance on the optimal use of radium-223 is provided.

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Prostate-specific antigen flare induced by cabazitaxel-based chemotherapy in patients with metastatic castration-resistant prostate cancer

Abstract

Background

Methods

Results

Conclusion

Introduction

Section snippets

Patients and methods

Population characteristics and outcomes of cabazitaxel therapy

Discussion

Conclusions

Conflict of interest statement

Acknowledgements

Lancet

Eur Urol

Ann Oncol Off J Eur Soc Med Oncol ESMO

Urology

Lancet Oncol

Current and emerging treatment modalities for metastatic castration-resistant prostate cancer

BJU Int

Phase I and pharmacokinetic study of XRP6258 (RPR 116258A), a novel taxane, administered as a 1-hour infusion every 3 weeks in patients with advanced solid tumors

Clin Cancer Res Off J Am Assoc Cancer Res

Preclinical antitumor activity of cabazitaxel, a semi-synthetic taxane active in taxane-resistant tumors

Clin Cancer Res

Cabazitaxel in metastatic castration-resistant prostate cancer

Expert Rev Anticancer Ther

Early PSA rise subsequently followed by PSA decline is a common event in prostate cancer patients responders to chemotherapy

Ann Oncol

Clinical significance of a prostate-specific antigen flare phenomenon in patients with hormone-refractory prostate cancer receiving docetaxel

Anticancer Drugs

Impact of PSA flare-up in patients with hormone-refractory prostate cancer undergoing chemotherapy

Int Urol Nephrol

Prostate-specific antigen flare phenomenon with docetaxel-based chemotherapy in patients with androgen-independent prostate cancer

BJU Int

PSA surge/flare-up in patients with castration-refractory prostate cancer during the initial phase of chemotherapy

Prostate