Impact of Progression at Baseline and On-Treatment Progression Events in Three Large Prostate Cancer Trials - Beyond the Abstract

Management of metastatic castration-resistant prostate cancer (mCRPC) has evolved in the past decade with 6 agents having demonstrated overall survival (OS) benefit in phase III trials and median OS from time to initiation therapy for mCRPC has increased from approximately one year in the 1990s to ~3 years in 2019.

Current guidelines and consensus conference reports recommend abiraterone or enzalutamide for asymptomatic/mildly symptomatic chemotherapy-naive men and chemotherapy is recommended for overtly symptomatic patients. An important challenge, however, is to determine when therapies should be initiated, halted or changed; and even the decision when to choose between a taxane or anti-androgen therapy in first-line can be difficult in daily practice.

Although the type of progression is collected at enrollment in most phase III trials, its impact on clinical outcomes had not been evaluated precisely. Moreover, criteria for disease progression weighted by importance vary in clinical practice leading towards different timing to initiate or switch therapy.

This prompted us to investigate two elements; Investigate the impact of the type of progression at the initiation of first-line docetaxel and cabazitaxel on survival outcomes. The second key element was to analyze the type of progression events during these taxane treatments. We performed a post-hoc analysis of 3 large trials for men with mCRPC; The TAX-327, VENICE and FIRSTANA trials.

The first outcome is that the type of progression at the initiation of first-line chemotherapy is a robust prognostic marker reflected by almost 1 year shorter median OS in patients with pain progression at baseline compared to patients with PSA progression only. In view of multiple lines of systemic treatment nowadays available, postponing initiation of chemotherapy or changing therapy despite repeated increases in PSA until either radiological or clinical progression may lead to missed windows of opportunity. Also, when patients become symptomatic they may no longer be able to receive a taxane-based treatment due to frailty, complications, bone events, or others. We believe these findings may help to decide on the initiation of first-line treatment.

Secondly, the study provides data about survival outcomes and on-treatment progression events with taxane-based chemotherapy, which has robust clinical implications. Pain and/or radiological progression preceding PSA progression as a first progression event during first-line chemotherapy occurred in ~ 55% of men. This finding is of pain progression as a first progression event in a substantial percentage of men is novel in mCRPC but in agreement with a post-hoc analysis of the CHAARTED study for patients with hormone sensitive prostate cancer,¹ indicating that one should be aware that clinical progression can precede PSA progression.

In daily practice, however, PSA is a leading parameter and imaging during treatment may not always be scheduled every 3 months as in clinical trials. Also, in the absence of PSA progression, imaging may not always be performed at the first signs of pain and the use of symptoms to guide therapy is not included in guidelines.  Therefore, these new data have the prospect to be practice changing and to be incorporated in clinical guidelines because it emphasizes regular visits and imaging, and not to rely on PSA progression alone.

Written by: Debbie G Robbrecht, MD, PhD,¹ Nicolas Delanoy, MD,² Ian F Tannock, MD, PhD,³ Bertrand Tombal, MD, PhD,⁴ Mario Eisenberger, MD,⁵ Karim Fizazi, MD, PhD,⁶ Oliver Sartor, MD,⁷ Florence Mercier, MD,⁸ Stephane Oudard, MD, PhD,⁹ Ronald de Wit, MD, PhD¹⁰

1. Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands. 
2. Medical Oncology, European Georges Pompidou Hospital, Paris, France. 
3. Medical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, CA, USA. 
4. Urology, Cliniques Universitaires St. Luc, Brussels, Belgium. 
5. Medical Oncology, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore, USA. 
6. Department of Cancer Medicine, Gustave Roussy Institute, Villejuif, France. 
7. Medicine and Urology, Tulane Cancer Center, New Orleans, LA, USA. 
8. Stat Process, Sanofi, Paris, France. 
9. Medical Oncology, European Georges Pompidou Hospital, Paris, France. 
10. Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands. 

1. Bryce et al, Patterns of PSA versus clinically progressive disease in the E3805 CHAARTED trial. Journal of Clinical Oncology. DOI: 10.1200/JCO.2018.36.15_suppl.5046 May 20, 2018. 5046-5046.