CUOS 2019: Sequencing Issues Around Androgen Receptor Pathway Inhibition

Toronto, Ontario ( Dr. Sebastien Hotte presented the latest research and expert opinions regarding the sequencing of agents in metastatic castrate-resistant prostate cancer (mCRPC).  There is currently no level one data to answer the question what the best sequence of therapy for mCRPC patients in this era is. However, based on previous analogous data, we can speculate on the next best logical steps in treatment in different scenarios:

  1. In non-metastatic CRPC setting after apalutamide or enzalutamide – we can either give abiraterone1 or docetaxel2.
  2. In denovo metastatic disease after abiraterone – we can give either enzalutamide3 or docetaxel4
  3. In denovo metastatic disease after docetaxel – we can give docetaxel re-challenge5, abiraterone or enzalutamide6, PARP inhibitor7, or Radium 2238
It is important to remember that a 1/3 of patients who are initially treated with abiraterone or enzalutamide harbor a primary resistance to this treatment. That is the reason that these patients should be monitored very closely, and if they are resistant to treatment, it should be promptly altered.

A retrospective analysis demonstrated the response rates of patients receiving initial treatment with hormonal therapy, docetaxel and cabazitaxel, and secondary hormonal treatment.9 The data demonstrated that rapid progression to CRPC (<12 months) was associated with a low response to secondary hormonal therapy. Additionally, PSA response to taxanes did not seem to be affected by the time for CRPC to develop.

Another study demonstrated a prognostic model for predicting response to abiraterone and overall survival in mCRPC patients. This proposed prognostic model identified six predictive factors:

  1. LDH> upper normal limit
  2. ECOG status 2 compared to 0-1
  3. Liver metastases present
  4. Albumin (<=4 g/dl vs. > 4 g/dl)
  5. Alkaline phosphatase > upper normal limit
  6. The time frame between starting androgen deprivation therapy (ADT) until the initiation of abiraterone is <=36 months compared to >36 months.
The next topic discussed was whether there is cross-resistance between androgen receptor pathway inhibitors. Two retrospective studies demonstrated that there is a poor response to abiraterone in patients who progressed on enzalutamide, with PSA reduction of more than 50% demonstrated in only 3% and 8% of patients in both studies.10,11 Furthermore, several retrospective studies also demonstrated a poor response to enzalutamide in patients progressing on abiraterone. These studies demonstrated a PSA reduction of more than 50% only in 16.7-28.6% of patients.12-15 Some evidence suggests that abiraterone before docetaxel decreases the efficacy of taxanes in mCRPC patients, as can be seen in figure 1.

Figure 1 – Does Abiraterone Before Docetaxel Decrease Efficacy of Taxanes in mCRPC Patients?
UroToday CUOS19 abiraterone before docetaxel mCRPC

In the ASCO meeting in 2017, a randomized phase 2 cross-over study of abiraterone + prednisone vs. enzalutamide for patients with mCRPC16 was presented (study schema is shown in figure 2). In this study mCRPC treatment naïve patients were randomized to either abiraterone or enzalutamide, and when progression was evident, they were switched to the other treatment. This study demonstrated that enzalutamide initially had better PSA response rates than abiraterone initially. However, no difference was discerned in the time to PSA progression between both groups. The authors also demonstrated that the detection of circulating tumor DNA was associated with measures of tumor burden and poor outcomes. Lastly, genomic alterations in BRCA2/ATM, TP53, PI3K pathway, RB1, and AR were associated with earlier progression and primary resistance.

Figure 2 – Study Schema of the Randomized Phase 2 Cross-over Study of Abiraterone + Prednisone vs. Enzalutamide for Patients with mCRPC
UroToday CUOS19 abiraterone plus prednisone vs. enzalutamide mCRPC

When assessing the results of the crossover in this study, PSA response rate and time to progression were better for 2nd line enzalutamide compared to 2nd line abiraterone. The sequence of abiraterone + prednisone followed by enzalutamide was associated with a trend toward a longer time to 2nd progression, and again, the presence of circulating tumor DNA was associated with worse outcomes. 

Dr. Hotte concluded his talk and summarized that there are currently multiple choices of treatment with little level one evidence to help with deciding which treatment sequence to use. Most probably, it is more prudent to start with abiraterone, if possible. In a patient with poor prognosis, starting therapy with taxanes should be considered. Most importantly, the multidisciplinary approach must be utilized with these patients for optimal treatment and outcomes. Lastly, these men still die due to mCRPC, and continuing to enroll in clinical trials is extremely important.

Presented by: Sebastien Hotte, MD, MSc (HRM), FRCPC, Lead and Co-Principal Investigator, McMaster Translational Research Team, Associate Professor, Department of Oncology, Division of Medical Oncology
McMaster University

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, Twitter: @GoldbergHanan at the CUOS – Canadian Uro-Oncology Summit 2019, #CUOS19 January 10-12, 2019 Westin Harbour Castle, Toronto, Ontario, Canada

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2. De Bono et al. Eur Urol 2017
3. De Bono et al. Eur Urol 2018
4. De Bono et al. Eur Urol 2017
5. Lavaud et al. Eur Urol 2018
6. Scher HI. Et al. NEJM 2012
7. Clarke et al. Lancet Oncol 2018
8. Sartor et al. Prostate 2016
9. Angelegus A et al. JCO 2014
10. Loriot Y et al. Ann Oncol 2013
11. Noonan KI et al. Ann Oncol 2013
12. Schrader A et al. Eur Urol 2014
13. Bianchini D et al. Eur J cancer 2014
14. Thomsen FB et al. Scand J Urol Nephrol 2014
15. Badrising S et al. Cancer 2014
16. Kim N et al. ASCO 2017