Which Patients with mCSPC Should Receive Chemotherapy?

(UroToday.com) In conjunction with the Scientific Congress held as part of the American Society of Clinical Oncology’s Annual Meeting in May 2020, an Educational Symposium was convened on August 8-10. In a session entitled “Sorting Through the Maze of Treatment Options for Metastatic Castration-Sensitive Prostate Cancer”, Dr. Carmel Jo Pezaro from Weston Park Hospital, Sheffield Teach Hospitals NHS Foundation Trust presented a plenary talk on selecting patients with metastatic castration sensitive prostate cancer (mCSPC) for chemotherapy.

Dr. Pezaro began by highlighting the journey of docetaxel in prostate cancer, beginning with the pivotal Tax-327 trial, published in 2004, which was the first study to demonstrate improvements in overall survival for men with metastatic castration-resistant prostate cancer (mCRPC). Since that time, subsequent studies have examined docetaxel earlier in the disease process, namely among patients with metastatic castration sensitive prostate cancer (mCSPC). These trials, GETUF-AFU15, CHAARTED, and STAMPEDE, have been extensively reported, discussed, and meta-analyzed previously. In aggregate, they demonstrate significant survival advantages for men who receive docetaxel for mCSPC, though secondary analyses have suggested that this may be restricted to men with high-volume disease.


Dr. Pezaro then highlighted each of these trials in mCSPC in somewhat more detail. The GETUG-AFU 15 trial recruited patients between October 2004 and December 2008. Patients received between 1 and 9 cycles of docetaxel, with a median of 8 cycles. 28% of the included cohort had prior local therapy and two-thirds had combined androgen blockade with LHRH agonist and first-generation non-steroidal anti-androgen. Approximately 50% had “good prognosis” on the basis of involvement of the axial skeleton. This trial differs from the other two in that it failed to demonstrate benefit to the addition of docetaxel in mCSPC (hazard ratio 1.01).

Chronologically, the next trial to accrue and report was CHAARTED. In CHAARTED, patients were recruited between July 2006 and December 2012. Those randomized to the experimental arm received 6 cycles of docetaxel, within 4 months of starting androgen deprivation therapy. Again, 28% of patients had prior local therapy with most receiving prostatectomy. 42% of patients received combined androgen blockade. An early amendment increased enrollment of patients with “bad prognosis” on the basis of disease volume. High-volume disease denoted patients with 4 or more bone metastasis including at least one outside the pelvis and spinal column or with visceral metastasis. Over a median follow-up of 29 months, there was significantly improved overall survival among those randomized to docetaxel (hazard ratio 0.61, 95% confidence interval 0.47 to 0.80) with similar outcomes at a longer 54 month follow-up (hazard ratio 0.72, 95% confidence interval 0.59 to 0.89).

The so-called “tie-breaker” trial was published in 2016 when STAMPEDE results were published. STAMPEDE is a multi-platform adaptive trial and the arms included in this analysis recruited between October 2005 and March 2013. Patients in the experimental arm received 6 cycles of docetaxel, beginning a median of 9 weeks after starting ADT. 60% of the included population had de novo metastatic disease with only 6% have received prior local therapy. 15% of the included patients received combined androgen blockade. Initial analyses of the whole study cohort found a significant survival benefit to docetaxel (hazard ratio 0.78, p = 0.006). Subsequent mature data on the M1 sub-cohort demonstrated similar results (hazard ratio 0.81, p = 0.009).

A pooled analysis from the STOPCAP group demonstrated a pooled 23% reduction in overall mortality for patients receiving docetaxel (hazard ratio 0.77, 95% confidence interval 0.6 to 0.87).


However, Dr. Pezaro pointed out that there are many remaining questions regarding the use of docetaxel in these patients. These include, non-exhaustively:

  1. Does volume matter: high-volume/risk may be more likely to benefit. Also, the trials used conventional imaging so the role of advanced imaging using PSMA-PET/CT may change assessment of disease volume.
  2. Does pattern of spread matter – ie. de novo (synchronous) vs relapse (metachronous) disease.
  3. Does biology matter – ie. genetic/genomic biomarkers.
  4. Do patient demographics matter?
  5. Does access to subsequent treatment matter?
  6. Does concomitant steroid use matter?
She then addressed these in sequence.

First, assessing the question of the effect of disease volume, the answer remains unclear. The pivotal trials which led to docetaxel use in this disease space (CHAARTED and STAMPEDE) defined metastatic disease volume on the basis of conventional imaging with computed tomography and bone scans. In spite of this, mature following up of these studies show conflicting results with benefits seen in patients with both high and low volume disease in the STAMPEDE cohort and benefit restricted to those with high volume disease in the CHAARTED cohort.


In terms of the effect of timing on docetaxel efficacy, Dr. Pezaro highlighted data from the French 030591 trial in which patients with rising PSA after local therapy failed to have benefited from docetaxel in either PSA-based progression-free survival or overall survival.


Dr. Pezaro then highlighted the question of how biology affects docetaxel efficacy. In both CHAARTED and STAMPEDE, approximately 10% of men had disease progression within 9 months. In mCRPC, cytokine and epigenetic changes have been associated with treatment resistance and poorer outcomes. Data in mCSPC are less mature and continue to emerge.



Dr. Pezaro then highlighted specific considerations to the use of cytotoxic chemotherapy in during COVID-19. First, prostate cancer occurs for the most part in a “vulnerable” population on the basis of demographic characteristics. Further, docetaxel is associated with neutropenia and infectious risk. Finally, social distancing rules in chemotherapy units have decreased treatment capacity. Further, real-world data regarding the use of docetaxel in mCRPC have suggested a greater toxicity burden and shorter survival than suggested from clinical trial data.

Dr. Pezaro stressed that not all men should receive docetaxel and that assessment of “chemo-fitness”. This includes an assessment of comorbidity, psychological health, physical function, cognitive function, nutrition, social support, all of which converge into treatment tolerance.


However, despite limitations to docetaxel, Dr. Pezaro stressed that docetaxel will benefit some men. In particular, the potential to layer therapy to increase the depth and duration of response is appealing. Further, increase genomic heterogeneity at the time of progression increases the change that some clones will be resistant to any given therapy. Finally, docetaxel is a cost-effective upfront strategy compared with abiraterone.


Presented by: Carmel Jo Pezaro, MBChB, Medical Oncologist, Weston Park Hospital, Sheffield Teach Hospitals NHS Foundation Trust

Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center Contact: @WallisCJD on Twitter the ASCO20 Virtual Education Program, #ASCO20, August 8-10, 2020.