ASCO 2018: Biochemical Recurrence: Judicious Clinical Management of an Evolving Disease State

Chicago, IL ( Alicia Morgans, MD gave an excellent talk on biochemical recurrence (BCR) in prostate cancer (PC) patients. The learning objectives of her talk included being able to recognize subsets of patients with BCR who may benefit the most from early treatment with androgen deprivation therapy (ADT), understanding the plethora of ADT complications, discovering the limitation of data available for considering the optimal timing of ADT in BCR, and lastly, recognizing that treatment of non-metastatic castrate resistant PC (M0CRPC) with novel androgen receptor (AR) directed therapy, is associated with prolonged metastasis free survival (MFS).

Dr. Morgans began with some background on PC and BCR. A total of 164,690 patients will be diagnosed with PC in the US in 2018. Approximately 15-40% will develop BCR within 10 years of initial treatment. Median time to BCR is 2-3 years, and it is most commonly an asymptomatic disease state. The landmark paper by Charles R. Pound, published in JAMA almost 20 years ago [1] described the natural history of almost 2000 men after radical prostatectomy (RP). A total of 315 patients developed BCR, and 34% of men with BCR developed metastasis. This paper produced highly significant median times that have been used ever since in describing the progression of these patients:

• Median time of 2-3 years from definitive treatment to BCR
• Median time of 8 years from BCR to metastasis
• Median time of 5 years from metastasis to death
• Median time of 13 years from BCR to death
• Median time of 15-16 years from definitive therapy to death

Most men with BCR did not develop metastasis during follow-up (although the length of follow-up was relatively short – with a median of only 5.3 years). Patient selection for treatment in BCR is critical. The risk of metastasis increases as PSA doubling time falls (figure 1). [2]

image 25

Dr. Morgans then continued to discuss the potential complication resulting from ADT. ADT causes low testosterone and estrogen levels, which cause all the associated adverse effects (Figure 2).

image 25b

The medical complications of ADT include sarcopenia, weight gain, decline in bone mineral density, increased fracture risk, increased risk of diabetes mellitus and cardiovascular disease, psychological effects, and cognitive changes. All these complications are almost identical to the features associated with frailty (Figure 3).

image 25c

The correct timing of systemic therapy (early vs. late) was next discussed by Dr. Morgans. The optimal time of ADT initiation remains undefined. Two retrospective studies found no benefit to immediate vs. late ADT for most patients. [3,4] One study found significant advantage to early ADT only when the PSA doubling time was less than 9 months. The TOAD trial is a randomized study comparing early vs. delayed ADT.[5] This study randomized 261 men to immediate and deferred ADT. The study was limited by failure to accrue, unadjusted analysis, and median PSA at ADT initiation in the delayed arm being higher than 30 ng/ml. This study failed to demonstrate any benefit to one of the treatment options.

Lastly, Dr. Morgans discussed the specific disease state of M0CRPC. She reviewed the recently published studies of PROSPER [6] and SPARTAN [7]. PROSEPR was a randomized double-blind phase 3 trial of enzalutamide+ADT compared to placebo+ADT in M0CRPC patients. The primary endpoint was MFS, and the study demonstrated a clear benefit to patients treated with enzalutamide with a median MFS of 36.6 s. 14.7 months, with a HR pf 0.29, p<0.001. Furthermore, enzalutamide was associated with stable to improved quality of life compared to placebo. The SPARTAN trial randomized M0CRPC patients to either placebo+ADT or Apalutamide+ADT, with a primary endpoint of MFS. Again, a clear benefit was demonstrated in favour of Apalutamide with median MFS of 40.5 vs. 16.2 months, with a HR of 0.28, p<0.001. Similarly to PROSPER, quality of life was maintained with the addition of Apalutamide.

Dr. Morgans concluded her excellent talk, stating that retrospective and prospective data are limited in guiding optimal timing of ADT in BCR. Patient selection for treatment of BCR is critical. Importantly, ADT is associated with reduced quality of life and medical complications that should be considered when making treatment decision together with patients. Lastly, treatment of M0CRPC with either enzalutamide or apalutamide is associated with prolonged MFS and maintenance of quality of life.

Presented by: Alicia Morgans, Northwestern University, Chicago, USA

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, Twitter:@GoldbergHanan at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA

1. Pound et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA, May 5, 1999-Vol 281, Number 17
2. Freedland SJ. et al. Risk of prostate cancer specific mortality following biochemical recurrence after radical prostatectomy. JAMA. 2005 Jul 27;294(4):433-9.
3. Fu AZ et al. Mortality and Androgen Deprivation Therapy as Salvage Treatment for Biochemical Recurrence after Primary Therapy for Clinically Localized Prostate Cancer. J Urol. 2017 Jun;197(6):1448-1454. doi: 10.1016/j.juro.2016.12.086. Epub 2016 Dec 19.
4. X. Garcia-Albeniz et al. Immediate versus deferred initiation of androgen deprivation therapy in prostate cancer patients with PSA-only relapse. An observational follow-up study. Eur J Cancer. 2015 May;51(7):817-24. doi: 10.1016/j.ejca.2015.03.003. Epub 2015 Mar 17.
5. Duchesne GM. Et al. Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial. Lancet Oncol. 2016 Jun;17(6):727-737. doi: 10.1016/S1470-2045(16)00107-8. Epub 2016 May 4.
7. Smith MR et al. Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. N Engl J Med. 2018 Apr 12;378(15):1408-1418. doi: 10.1056/NEJMoa1715546. Epub 2018 Feb 8.