Athens, Greece ( Dr. Mehmet Ali Nahit Sendur summarized the role of androgen deprivation therapy (ADT) in the era of the androgen receptor axis targeted therapy (ARAT). The critical role of androgens has been well established in stimulating prostate cancer growth. Therefore, ADT has been used in the treatment of metastatic prostate cancer. ADT can normalize serum levels of prostate-specific antigen in over 90% of patients and can produce objective tumor responses in 80-90% of patients. ADT can also reduce bone pain and decreases the rate of complications caused by prostate cancer metastases.

The duration of response to ADT in metastatic patients is highly variable, and eventually most experience disease progression despite treatment. The progression is to the castrate-resistant state, although such tumors may remain responsive to additional therapies directed against the androgenic stimulation of prostate cancer. 

Hormonal therapy is currently recommended for the management of hormone-naïve metastatic, recurrent, or progressive prostate cancer. Two types of hormonal therapy are recommended, either bilateral orchiectomy or castration with luteinizing hormone-releasing hormone (LHRH) agonists or antagonists. Antiandrogen monotherapy appears to be less effective than medical and surgical castration and is not recommended as primary ADT. Currently, there is no level one evidence guiding us how to choose between LHRH agonists or antagonists, except in patients with impending spinal cord compression, who require antagonists, or bilateral orchiectomy.

The concept of intermittent hormonal therapy was first introduced in 20131, and it allows low-risk patients to take breaks between hormonal treatments. Intermittent ADT did not end up being inferior to continuous ADT, but it did present a small improvement in the quality of life.1

Moving on, Dr. Ali Nahit Sendur presented two important questions:

  1. Can we increase the efficacy of ADT?
  2. Can we omit ADT in the era of ARAT and docetaxel?

The development of additional therapies has resulted in their use in the initial therapy of metastatic patients. As previously mentioned, ADT is continuously provided throughout all the stages of the disease, on top of these newly used medications (Figure 1). Continuous ADT is important, even in the castrate-resistant status, as within the prostate and prostate tumor microenvironment androgen activity continues even when serum testosterone levels are suppressed by ADT. Intracrine androgen synthesis is enough to activate androgen receptor target genes, and therefore they need to be blocked by using ADT.

It is important to remember that castrate-resistant does not mean that it is hormone-resistant. In fact, the theory of continuing ADT when initiating chemotherapy in mCRPC patients is that pausing ADT may lead to renewed release of testosterone and stimulation of the remaining androgen-sensitive elements of the tumor. Conversely, approximately 50% of men treated with ADT in the long-term remain castrated for 2.5 years after stopping ADT. In contrast, stopping ADT might re-induce hormone sensitivity, and that is why continuation of ADT is recommended.

Figure 1 – The importance of androgen deprivation therapy throughout all disease stages.

SIU 2019 androgen deprivation all disease stagesJPG

Unfortunately, there are many adverse effects associated with ADT and they can be quite bothersome to the patient (Figure 2). These range from metabolic effects, to loss of libido, fatigue, hot flashes, osteoporosis and more.

Figure 2 – Androgen deprivation therapy adverse effects:

SIU 2019 Androgen deprivation therapy adverse effects

The last topic discussed by Dr. Ali Nahit Sendur was whether it was possible to omit ADT therapy in these metastatic patients. The SPARE trial is exploring the role of continuing ADT when starting treatment with abiraterone +prednisone in asymptomatic chemo-naïve mCRPC patients.2 There are retrospective data showing that abiraterone + prednisone alone without ADT was able to effectively suppress testosterone synthesis in prostate cancer patients. Withholding ADT did not seem to compromise outcomes. However, as this is retrospective data, and until we have level one prospective evidence, the guidelines will continue to recommend treatment with ADT in mHSPC and mCRPC patients, despite any newly added treatment.

In conclusion, in metastatic disease, while hormonal treatment improves symptoms, there is no conclusive prospective evidence to date, that lowering testosterone levels improves life expectancy. The current recommendation is to continue hormonal treatment for life in metastatic prostate cancer patients.

Presented by: Mehmet Ali Nahit Sendur, MD, Department of Basic Medical Oncology, Ankara Yildirim Beyazit University, Ankara, Turkey

Written by: Hanan Goldberg, MD, Urology Department, SUNY Upstate Medical University, Syracuse, New-York, USA @GoldbergHanan at the 39th Congress of the Société Internationale d’Urologie, SIU 2019, #SIUWorld #SIU2019, October 17-20, 2019, Athens, Greece

1. Hussain M, Tangen CM, Berry DL, et al. Intermittent versus Continuous Androgen Deprivation in Prostate Cancer. New England Journal of Medicine 2013; 368(14): 1314-25.
2. Ohlmann CH, Jaschke M, Jaehnig P, et al. Abiraterone acetate plus LHRH therapy versus abiraterone acetate while sparing LHRH therapy in patients with progressive, metastatic and chemotherapy-naive, castration-resistant prostate cancer (SPARE): study protocol for a randomized controlled trial. Trials 2017; 18(1): 457.