2. UroToday Home
  3. Recent Abstracts
  4. Urologic Oncology
  5. Prostate Cancer

Improving the management of patients with prostate cancer receiving long-term androgen deprivation therapy, "Beyond the Abstract," by Claude C. Schulman MD, PhD, et al

BERKELEY, CA (UroToday.com) - Many patients with prostate cancer (PCa) currently receive long-term androgen deprivation therapy (ADT) for advanced disease or as an adjuvant to radiotherapy for high-risk localized or locally advanced disease. However, ADT is associated with well-established side effects which may reduce quality of life (QoL). Our review examined strategies for improving the management of patients undergoing long-term ADT by minimising the impact of these side effects.

Intermittent androgen deprivation (IAD) offers an alternative to continuous ADT (CAD) by separating ADT treatment periods with periods where treatment is withdrawn to allow testosterone recovery. The aim is to minimize side effects and improve QoL without compromising efficacy. However, the clinical evidence supporting IAD has been rather conflicting. Initial phase III studies suggested similar overall survival for IAD and CAD,[1] although the power of these studies to detect differences in long-term outcomes has been questioned.[2] More recent data from two large phase III trials – SWOG JPR.7[3,4] and SEUG 9401[5,6] – have shown a beneficial effect of IAD on treatment-related side effects (e.g. hot flashes and sexual dysfunction) and overall QoL vs. CAD, with no negative impact on overall survival. Interestingly, there were slightly more cancer-related deaths with IAD in both trials, however, this was offset by a slightly higher rate of non-cancer-related deaths (SWOG JPR.7) or deaths from cardiovascular/other causes (SEUG 9401) with CAD. Data from these trials, together with the phase III SEUG 9901 study and other analyses, suggest better tolerability, and possibly QoL, with IAD vs. CAD.

Recent results from the FinnProstate study VII in locally advanced/metastatic PCa further support the similar efficacy of IAD and CAD,[7] showing no significant between-group differences in overall or PCa-related deaths at a median 65-month follow-up. While IAD was associated with some QoL advantages vs. CAD, there was no significant difference between treatments in the prevalence of adverse events,[8] although erectile dysfunction was more frequent with IAD. It has been suggested that, compared with previous trials, the apparent lack of a clear benefit regarding drug-related adverse effects in this study may reflect differences between trials in durations of ‘normal’ testosterone levels during off-treatment periods.[9] Moreover, in contrast to initial expectations, Mottet[9] suggests that, for IAD, “the real QoL benefit appears to be at best marginal, if any.” Furthermore, the author suggests that, as many men maintain low testosterone concentrations (but above castration level) during off-treatment periods, this may help explain the apparent lack of clear benefits.[9] In line with this, in SWOG JPR.7, full testosterone recovery (to pre-treatment levels) occurred in only 35% of patients undergoing IAD.[3] Of note, recent results of the large SWOG 9346 trial found that IAD was not non-inferior to CAD in patients with metastatic PCa (median survival 5.8 vs. 5.1 years and 10-year survival was 29% vs. 23%, for CAD vs. IAD, respectively).[10] Interestingly, while IAD was non-inferior to CAD in patients with extensive disease, CAD was found to be significantly better than IAD in those with minimal disease.[10]However, caution is necessary when interpreting these exploratory subgroup findings and further confirmatory studies are required. Preliminary QoL results for SWOG 9346 at 3 months post-randomisation were in agreement with previous trials, showing better sexual function in patients undergoing IAD vs. CAD.[11]

Current European Association of Urology (EAU) guidelines state that IAD should no longer be considered investigational and these also provide guidance regarding the length of the initial (induction) cycle and criteria for stopping and resuming treatment.[12] However, they acknowledge that current PSA thresholds are empirical and that clarification is required to better define the initial treatment period, optimal PSA triggers for stopping and restarting therapy, and the selection of appropriate patients for IAD. Furthermore, EAU guidelines state that gonadotrophin-releasing hormone (GnRH) antagonists may be a valid alternative to agonists if clear results are obtained from randomized trials. Degarelix, the first of a new generation of GnRH antagonists, produces rapid testosterone and PSA suppression without the agonist-induced testosterone surge (flare); this rapid PSA suppression make degarelix a suitable candidate for IAD. Phase III IAD trials of this agent are ongoing and results are eagerly awaited.

Another consideration in patients undergoing long-term ADT, is how best to manage the associated bone-related complications. Osteoporosis (and the resultant increased fracture risk) is a well-recognized complication of long-term ADT,[13] therefore, bone mineral density should be measured before and during treatment and patients advised to make appropriate lifestyle changes to help preserve bone health. Therapies that inhibit osteoclast activity can also alleviate the skeletal complications of ADT. Current treatment options include bisphosphonates (e.g. zoledronate) and the receptor activator of NF-κB ligand (RANKL) inhibitor, denosumab. In patients whose disease has metastasized, zoledronate and denosumab are both licensed to prevent skeletal-related events, although a large randomized study recently showed that denosumab was more effective than zoledronate in this setting.[14] Denosumab is also currently the only agent specifically approved for the prevention of ADT-induced bone loss in patients with non-metastatic disease who are at increased risk of fracture. Furthermore, denosumab recently became the first agent to demonstrate the prevention of bone metastases in patients with PCa,[15] although it is not currently licensed in this setting.

In summary, IAD and agents to protect bone health are strategies that should be considered to improve the risk:benefit ratio of long-term ADT. While some trials (SWOG 9346) suggest a difference in metastatic patients, currently the data in M0 patients show no superiority of one strategy over the other regarding overall survival, and most showed a better tolerability with IAD, although definitive evidence of the tolerability and QoL benefits remains to be fully established. Furthermore, the optimal IAD treatment parameters in terms of patient selection, criteria for stopping/restarting ADT, and type of ADT remain to be defined. The efficacy and tolerability profile of newer ADTs during IAD is also yet to be established. Importantly, various agents have now been shown to be effective in preventing skeletal-related events in patients with metastatic PCa undergoing ADT, including denosumab and zoledronic acid.[16] Denosumab is also licensed to reduce ADT-induced bone loss in patients with non-metastatic disease at increased risk of fracture. Together, these strategies may help to improve the overall tolerability of long-term ADT.  

References:

  1. Abrahamsson PA. Potential benefi ts of intermittent androgen suppression therapy in the treatment of prostate cancer: a systematic review of the literature. Eur Urol 2010;57:49–59
  2. Shore ND, Crawford ED. Intermittent androgen deprivation therapy: redefining the standard of care? Rev Urol 2010;12:1–11
  3. Crook JM, et al. Intermittent androgen suppression for rising PSA level after radiotherapy. N Engl J Med 2012;367:895-903
  4. Klotz L, et al. A phase III randomized trial comparing intermittent versus continuous androgen suppression for patients with PSA progression after radical therapy: NCIC CTG PR.7/SWOG JPR.7/CTSU JPR.7/UK Intercontinental Trial CRUKE/01/013. J Clin Oncol Genitourinary Cancers Symposium 2011;29 (7 suppl): abstr 3
  5. Calais da Silva FE, et al. Intermittent androgen deprivation for locally advanced and metastatic prostate cancer: results from a randomised phase 3 study of the South European Uroncological Group . Eur Urol 2009;55:1269–77
  6. Calais da Silva FM, et al. Phase III study of intermittent MAB vs continuous MAB. J Urol 2011;185:e288 (abstr 716)
  7. Salonen AJ, et al. The FinnProstate Study VII: intermittent versus continuous androgen deprivation in patients with advanced prostate cancer. J Urol 2012;187(6):2074-81
  8. Salonen AJ, et al. Advanced prostate cancer treated with intermittent or continuous androgen deprivation in the randomised FinnProstate Study VII: quality of life and adverse effects. Eur Urol. 2012 Jul 27. [Epub ahead of print]
  9. Mottet N. Intermittent Androgen Deprivation Therapy in Prostate Cancer: Is Everything So Clear? Eur Urol. 2012 Aug 14. [Epub ahead of print]
  10. Hussain M, et al. Intermittent (IAD) versus continuous androgen deprivation (CAD) in hormone sensitive meta-static prostate cancer (HSM1PC) patients (pts): results of S9346 (INT-0162), an international phase III trial. J Clin Oncol 2012;30(Suppl),abstract LBA 4
  11. Moinpour C, et al. Preliminary quality-of-life outcomes for SWOG-9346: Intermittent androgen deprivation in patients with hormone-sensitive metastatic prostate cancer (HSM1PC)—Phase III. J Clin Oncol 30, 2012 (suppl; abstr 4571)
  12. Heidenreich A , et al. Guidelines on prostate cancer. February 2012. Available from www.uroweb.org/gls/pdf/08_Prostate_Cancer.pdf  (Accessed September 2012 )
  13. Isbarn H, et al. Androgen deprivation therapy for the treatment of prostate cancer: consider both benefi ts and risks. Eur Urol 2009;55:62–75
  14. Fizazi K, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 2011;377:813–22
  15. Smith MR, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet 2012;379:39–46
  16. Aapro M, Saad F. Bone-modifying agents in the treatment of bone metastases in patients with advanced genitourinary malignancies: a focus on zoledronic acid. Ther Adv Urol 2012;4:85-101

 

Written by:
C. Schulman,* J. Irani,† and M. Aapro‡ as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

*Clinic Edith Cavell, University of Brussels, Brussels, Belgium
†Urology Unit, University Hospital, Poitiers,France, and
‡Institut Multidisciplinaire d’ Oncologie IMO, Clinique de Genolier, Genolier, Switzerland

Improving the management of patients with prostate cancer receiving long-term androgen deprivation therapy - Abstract

More Information about Beyond the Abstract