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Improving on Cabazitaxel Chemotherapy for Metastatic Prostate Cancer – Studying Novel Combinations

For men with metastatic castration-resistant prostate cancer, there are limited options for treatment after progression on docetaxel chemotherapy.  Fortunately, cabazitaxel is another taxane chemotherapy that offers a survival benefit in the post-docetaxel setting over mitoxantrone in the TROPIC trial.1 The initial concern was a 7.5% febrile neutropenia rate and a 4.9% toxic death rate.  However, this concern has been ameliorated with increased utilization of growth factor prophylaxis, and the PROSELICA trial showed non-inferiority of 20 mg/m2 dosing compared with the 25 mg/m2 dosing in regards to overall survival, with much lower toxicity.2

Recently, the CARD trial revealed a progression-free and overall survival benefit of cabazitaxel over a second novel hormonal agent (e.g. abiraterone acetate or enzalutamide) in patients who previously received another novel hormonal agent and docetaxel.3  This trial was essentially positive in all key endpoints, including prostate-specific antigen (PSA) decline rate, RECIST 1.1 response rate and pain response even though cabazitaxel was dosed at 25 mg/m2 with growth factor prophylaxis and a resultant adverse event discontinuation rate of 19.8% compared with 8.9% for the novel hormonal agent.  However, the eligibility criteria for the trial did mandate patients progress within 1 year of starting their prior novel hormonal agent.  This led to a rather poor prognostic patient demographic where initial duration of androgen deprivation therapy to castration-resistance was rather short at a median ~13 months.  Additionally, ~70% of patients entered on the trial with symptomatic pain progression.  Regardless, cabazitaxel is an ideal 3rd line therapy choice for patients with metastatic castration-resistant prostate cancer, and is a definitive standard for those with more aggressive clinical features.

There have been very few combination trials that include cabazitaxel chemotherapy.  This may be partially due to our prior track record, previously lacking success with docetaxel combination therapies. I previously outlined this topic in last month’s Clinical Trials Portal.4  However, there are unique subsets of patients, such as neuroendocrine/small cell and aggressive variant prostate cancers, that appear susceptible to the specific combination of docetaxel with carboplatin.5 This similar concept has been recently imported to combine carboplatin with cabazitaxel, and the phase 1 dosing led to the recommended phase 2 dose of carboplatin AUC 4 with cabazitaxel 25 mg/m2 every 3 weeks.6  It was also demonstrated in the randomized phase 2 portion of that trial that cabazitaxel plus carboplatin (n=81) improved median progression-free survival to 7.3 months (95% CI 5.5-8.2; HR 0.69, 95% CI 0.5-0.95, p=0.018) when compared to cabazitaxel alone, which had a median progression-free survival of 4.5 months (95% CI 3.5-5.7).  Interestingly, neuroendocrine/small cell prostate cancer patients were allowed on that trial, and over half the patients met aggressive variant prostate cancer clinicopathological criteria.  As a result of this data, a randomized phase 3 trial is in planning.

Although carboplatin is promising in combination with cabazitaxel, other trials have combined novel hormonal agents with cabazitaxel.  Some have completed accrual and have yet to report on final results.  Recently, an abstract presented at the 2020 Genitourinary Cancers Symposium revealed the combination of cabazitaxel with enzalutamide to yield very high PSA response rates.  The > 90%, > 50%, and > 30% PSA decline rates were 56%, 78%, and 81%, respectively, in this open-label phase 2 trial that included many patients previously treated with abiraterone acetate and/or prior docetaxel for metastatic hormone-sensitive prostate cancer.7 

As we peruse the actively accruing cabazitaxel combination trials below, all of them are combinations with either carboplatin, novel hormonal agents or both. We should accrue to these trials and begin to design others creative combinations, as the role of cabazitaxel has become stronger for advanced metastatic castration-resistant prostate cancer, and the agent may well be imported into even earlier disease states with successful future investigations.

Highlighted cabazitaxel combination trials for metastatic prostate cancer patients include: 

  • CASCARA trial – Phase 2 trial of Cabazitaxel plus carboplatin followed by abiraterone with prednisone in metastatic hormone-sensitive prostate cancer (NCT03934840)
  • Phase 2 randomized trial of Abiraterone plus antiandrogen +/- cabazitaxel with prednisone for metastatic castration-resistant prostate cancer previously treated with docetaxel (NCT03419234)
  • Phase 2 trial of Cabazitaxel, carboplatin and prednisone followed by olaparib maintenance for aggressive variant prostate cancer (NCT03263650)
  • Phase 1 trial of PACE (Prednisone, Abiraterone, Cabazitaxel either 15 or 20 mg/m2, and Enzalutamide) for first-line metastatic castration-resistant prostate cancer (NCT03110588)
  • Phase 2 trial of PRINT (3-month cycling of abiraterone followed by Cabazitaxel plus Carboplatin followed by Enzalutamide plus Radium-223) for metastatic castration-resistant prostate cancer (NCT02903160)
Written by: Evan Yu, MD, Professor, Department of Medicine, Division of Oncology, University of Washington School of Medicine, Member, Clinical Research Division, Fred Hutchinson Cancer Research Center, Clinical Research Director, Genitourinary Oncology, Seattle Cancer Care Alliance, Medical Director, Clinical Research Service, Fred Hutchinson Cancer Research Consortium

References: 

  1. De Bono JS et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 2010; 376:1147-54.
  2. Eisenberger M et al. Phase III Study Comparing a Reduced Dose of Cabazitaxel (20 mg/m2) and the Currently Approved Dose (25 mg/m2) in Postdocetaxel Patients With Metastatic Castration-Resistant Prostate Cancer—PROSELICA. J Clin Oncol 2017; 35:3198-206.
  3. De Wit R et al. Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer. N Engl J Med 2019; 381:2506-18.
  4. Yu EY.  Urotoday 2020; Clinical Trials Portal, Online, July 1, 2020.
  5. Aparicio AM et al. Platinum-Based Chemotherapy for Variant Castrate-Resistant Prostate Cancer. Clin Cancer Res 2013; 19:3621-30.
  6. Corn PG et al. Cabazitaxel plus carboplatin for the treatment of men with metastatic castration-resistant prostate cancers: a randomised, open-label, phase 1-2 trial. Lancet Oncol 2019; 20:1432-43.
  7. Graff JN et al. Phase II study of cabazitaxel (CAB) plus enzalutamide (ENZ) in metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol 38, no. 6_suppl (February 20, 2020) 86-86