Article Index

Staged and Confused: Sequencing of Therapy in Metastatic Castration-Resistant Prostate Cancer

Zachary Post, PharmD
PGY1 Pharmacy Practice Resident
Louis Stokes Cleveland VA Medical Center
Cleveland, OH

Prostate cancer is the most prevalent cancer among North American men and accounts for the second highest number of deaths from any type of cancer.1 In 2015, there is estimated to be a total of 220,800 new prostate cancer cases diagnosed, resulting in nearly 30,000 deaths in the United States. Prostate cancer is associated with significant morbidity and mortality, which increases as the disease progresses. After prostate cancer becomes metastatic, the estimated 5-year overall survival (OS) is approximately 31%, down from 100% with early-stage disease.2

The cornerstone of treatment is androgen deprivation therapy (ADT).2 Androgens, including testosterone, are taken up by cells within the prostate and bind to the androgen receptor (AR) to promote function and growth. Activation of the AR can promote the growth of both normal and cancerous prostate cells, allowing androgens to play a role in the development and progression of prostate cancer.3,4  For this reason, many treatment regimens for prostate cancer target the AR signaling pathway.

ADT can be surgical or medical; the most common medical approach is treatment with a gonadotropin- releasing hormone (GnRH) modulator, such as leuprolide, goserelin, or degarelix.2,5  These agents suppress luteinizing hormone production and, thereby, the synthesis of testicular androgens through stimulation or inhibition of GnRH.

Although the majority of prostate cancer initially responds to ADT, cancer cells can become resistant to treatment and survive and grow under low levels of circulating testosterone.2,4,5  This is defined as castration-resistant disease. Castration-resistant disease is still driven by AR signaling; therefore, ADT should be continued indefinitely and other chemohormonal therapies should be initiated.  The focus of this review will be on treatment options and data behind sequencing strategies for metastatic castration-resistant prostate cancer (mCRPC).

Treatment Options for Metastatic Castration-Resistant Prostate Cancer

Docetaxel (DOC), a microtubule stabilizer, became the standard treatment for mCRPC with the TAX327 trial, which was the first trial to demonstrate an OS benefit with chemotherapy in mCRPC.6 After its initial approval in 2004, there were several years without any new agents approved for mCRPC. Recently, several agents with novel mechanisms have gained approval for use in mCRPC treatment (Table 1).

Cabazitaxel (CAB) is an intravenous agent with a similar mechanism of action as DOC, how- ever it has antitumor activity in mCRPC refractory to DOC therapy.7 In 2010, TROPIC be- came the first trial to demonstrate an OS benefit in the post-DOC setting, comparing CAB Table 1. Novel Chemohormonal Therapy Options Currently Available for mCRPC combined with prednisone to mitoxantrone combined with prednisone. CAB, in combination with prednisone, received U.S. Food and Drug Administration (FDA) approval for use following DOC and, to date, CAB carries only that indication. Abiraterone (ABI) and enzalutamide (ENZ) are both oral agents that inhibit androgen synthesis via different mechanisms. ABI binds and inhibits CYP17A1, a critical component in both the testicular and extragonadal androgen synthesis pathways, while ENZ binds to the AR and serves as a potent androgen antagonist, preventing ligand-bound AR translocation into the nucleus.8–11  ABI was the first of these two agents to gain FDA approval for mCRPC following DOC therapy with COUGAR

301, in which it was compared to placebo with prednisone.8 ENZ was studied in a similar manner and first gained approval following DOC treatment with the results of the AFFIRM trial in 2012.10  Later in 2012, COUGAR 302 became the first trial to trigger regulatory approval of an additional first-line agent, ABI, in mCRPC.9 As of late 2014, with the release of results from the PREVAIL trial, ENZ also carries the indication for first-line treatment of mCRPC.11  Sipuleucel- T and radium-223 were approved for mCRPC in 2010 and 2013, respectively.12,13  These agents have very unique mechanisms, and their use is limited to a small subset of patients.

The Confusion

With the increase in approved agents during the past 5 years, there is much uncertainty about the optimal treatment sequence. Prostate cancer is a progressive disease during which many patients will endure multiple lines of therapy, requiring practitioners to make informed clinical decisions when selecting treatment regimens. Further investigation of suspected resistance mechanisms also is warranted because they have yet to be fully characterized. For these reasons, it is important to search for the appropriate sequences in which to use these therapies when treating patients with mCRPC.

The National Comprehensive Cancer Network (NCCN), American Urological Association (AUA), and American Society of Clinical Oncology (ASCO) have recently updated their guidelines.2,5,14  Although these resources recommend the use of the aforementioned therapies, they do not provide guidance in terms of sequencing agents other than suggesting that clinicians consider the previous treatments, presence or absence of visceral metastases, symptoms, patient preference, and potential side effects when selecting therapies.5,14  The ASCO guidelines highlight the importance of continuous ADT, while outlining the available first- line chemohormonal therapies.2 Unfortunately, the guideline fails to provide guidance about which agent to initiate after the patient progresses past any first-line, or even second-line treatment. Practitioners are left with scarce data from retrospective studies to guide treatment decisions.

Therapy Sequencing

All published studies regarding therapy sequencing in mCRPC are retrospective, single-arm studies (Table 2).15–22 Patients included in these studies had progressive mCRPC with similar baseline characteristics, including: median ages of 65–72 years, Gleason scores 6–9, and Eastern Cooperative Oncology Group performance status scores of 0–2.

Third-Line ENZ (DOC  ABI  ENZ)

There are three published retrospective studies reviewing the use of third-line ENZ in patients with progressive mCRPC after previous treatment with DOC and ABI.17–19 Although less robust than in the second-line setting, these studies have revealed a response to third- line ENZ.17–19  Prostate-specific antigen (PSA) responses, defined by the Prostate Cancer Clinical Trials Working Group as a >50% decline from baseline PSA, were less than those seen with second-line ENZ therapy in the AFFIRM trial.10  In AFFIRM, 54% of patients experienced a PSA response with ENZ, whereas 17%–45.7% of patients had the same response to third-line ENZ.10,17–19

The lower PSA response rates were thought to be due to cross- resistance between ABI and ENZ.17–19  Response to previous therapy was not found to be predictive of response to ENZ. For example, of the 16 (45.7%) patients in the study by Schrader and colleagues with a PSA response to ENZ, 43.8% previously had a PSA response to ABI and 13.8% did not.17

Third-Line ABI (DOC  ENZ  ABI)

One study by Noonan and colleagues investigated the third-line use of ABI for progressive mCRPC after previous treatment with DOC and ENZ.20  In contrast to the ENZ studies, the primary endpoint was a PSA response of >30% from baseline, with only three (11%) patients meeting that endpoint. In addition, only 4% of patients had a >50% PSA decline with third-line ABI, which was less than the 29.5% of patients who had the same response from second-line ABI in COU- GAR 301.8 The poor responses seen in the study by Noonan and col- leagues20  and the minimal, but apparent, responses seen with the previous studies may suggest that second-line ABI followed by third-line ENZ may be the more favorable treatment sequence. These data must be confirmed with larger, randomized sequencing studies.

Third-Fourth-Line CAB (DOC  ABI [ENZ]  CAB)

There are two published studies reviewing the third-line use of CAB after DOC and ABI therapy.21,22 Sella and colleagues investigated third-line CAB after previous treatment with DOC and ABI.21  The duration of CAB therapy was comparable to the TROPIC study, which evaluated second-line CAB therapy.7 PSA responses of >50% were similar between both studies, with 31.5% of patients in Sella and colleagues and 39.2% of patients in TROPIC achieving this response. Despite similar PSA responses, the median OS in Sella and colleagues' study (8.2 months, 95% CI: 3.34–13.05) was shorter than in the TROPIC trial (15.1 months, 95% CI, 14.1–16.3).

Nakouzi and colleages cumulatively investigated third- and fourth- line CAB after previous treatment with DOC, ABI, and ENZ.22  Al- though dosage and duration were not specified, this study included six (7.6%) patients who received ENZ before fourth-line CAB. Similar to the aforementioned study, the duration of CAB therapy in Nakouzi et al. was comparable to that in TROPIC.7 PSA responses of >50% were seen in 35% of patients, and median OS was shorter in Nakouzi and colleagues' study (10.9 months, 95% CI: 8–14) than in TROPIC (15.1 months, 95% CI: 14.1–16.3). However, median progression-free survival of 4.4 months (95% CI: 3.5–5.2) in Nakouzi and colleagues' was longer than the 2.8 months (95% CI: 2.4–3.0) seen in the TROPIC study.

Although the results of Sella and colleagues and Nakouzi and colleagues do not adequately address CAB in the third- and fourth-line setting due to the limited number of patients, these data suggest that CAB retains activity after prior treatment exposure. The optimal place in therapy for CAB requires further investigation.

Future Directions

Several sequences and combinations have not yet been addressed in the literature. Studies continue to investigate therapies in mCRPC, including the active phase 3 trial (NCT01949337) of ENZ monotherapy against the combination of ENZ, ABI, and prednisone in recurrent mCRPC.23  Along with new combinations and sequencing strategies being investigated, there also are a few new agents in the pipeline for treatment of mCRPC. Oral agents cabozantinib and tasquinimod and subcutaneous vaccine PROSTVAC-V/ F are being studied in phase 3 clinical trials for use in mCRPC.24  Cabozantinib is a tyrosine kinase inhibitor that targets met proto-oncogene and vascular endothelial growth factor receptor 2 and is FDA-approved for use in medullary thyroid carcinoma.25  It is being studied for third-line use in mCRPC after failure of DOC and either ABI or ENZ.24,25  Tasquinimod binds and inhibits S100A9, a calcium-binding protein implicated in prostate cancer, while PROSTVAC-V/ F contains transgenes for PSA as the target tumor antigen.24  Both agents are being studied for first-line use in mCRPC against placebo. The potential approval of new agents for this indication will certainly add more confusion for providers when initiating treatment and sequencing subsequent therapies.


Prostate cancer is a progressive and potentially deadly disease. Chemo-hormonal therapies result in improved survival for patients with mCRPC, but there is limited evidence for guiding treatment decisions after patients progress beyond first- or even second-line therapy. At this time, there is insufficient evidence to designate the optimal sequence or combination of therapies in mCRPC. Current data regarding sequencing are from retrospective, single-arm studies and offer limited guidance in the third- and later-line settings.17–22  There is likely some cross-resistance between agents, which may be lessened when using ABI before ENZ.20  CAB appears to retain some activity in the third-line setting after treatment with DOC and ABI.21,22  When making treatment decisions, providers must take clinical trial evidence along with patient factors and agent-specific characteristics into consideration. In addition, the identification of appropriate predictors for response to these agents is still needed for clinical trials. Prospective, head-to-head trial comparisons addressing cross-resistance and therapy sequencing are needed to make definitive, evidence-based recommendations for patients with mCRPC.


  1. Howlander N, Noone AM, Kapcho M, et al. SEER Cancer Statistics Review, 1975–2012. Bethesda, MD: National Cancer Institute. Based on November 2014 SEER data submission, posted to the SEER website. Accessed April 15, 2015.
  2. Basch E, Loblaw A, Oliver TK, et al. Systemic therapy in men with metastatic castration-resistant prostate cancer: American Society of Clinical Oncology and Cancer Care Ontario clinical practice guideline. J Clin Oncol. 2014;32:3436-3448.
  3. Genetics of prostate cancer–for health professionals (PDQ®). Bethesda, MD: National Cancer Institute. hp/prostate-genetics-pdq. Updated February 10, 2015. Accessed February 15, 2015.
  4. Prostate cancer treatment–for health professionals (PDQ®). Bethesda, MD: National Cancer Institute. hp/prostate-treatment-pdq. Updated October 28, 2014. Accessed February 15, 2015.
  5. Cookson MS, Roth BJ, Dahm P, et al. Castration-resistant prostate cancer: AUA guideline. J Urol. 2013;190:429-438.
  6. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502-1512.
  7. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376:1147-1154.
  8. Fizazi K, Scher HI, Molina A, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2012;13:983-992.
  9. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med.2013;368:138-148.
  10. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-1197.
  11. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371:424-433.
  12.  Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.
  13. Parker C, Nilsson S, Heinrich ND, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369:213-233.
  14. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer [version 1.2015]. prostate.pdf. Published October 24, 2014. Accessed December 9, 2014.
  15. Scher HI, Halabi S, Tannock I, et al. Design and endpoints of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the prostate cancer clinical trials working group. J Clin Oncol. 2008;26:1148-1159.
  16. Venook AP, Tabernero J. Progression-free survival: helpful biomarker or clinically meaningless end point? J Clin Oncol. 2015;33:4-6.
  17. Schrader AJ, Boegemann M, Ohlmann CH, et al. Enzalutamide in castration-resistant prostate cancer patients progressing after docetaxel and abiraterone. Eur Urol. 2014;65:30-36.
  18. Thomsen FB, Røder MA, Rathenborg P, Brasso K, Borre M, Iversen P. Enzalutamide treatment in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy and abiraterone acetate. Scand J Urol. 2014;48:268-275.
  19. Badrising S, van der Noort V, van Oort IM, et al. Clinical activity and tolerability of enzalutamide (MDV3100) in patients with metastatic, castration-resistant prostate cancer who progress after docetaxel and abiraterone treatment. Cancer. 2014;120:968-975.
  20. Noonan KL, North S, Bitting RL, Armstrong AJ, Ellard SL,Chi KN. Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide. Ann Oncol. 2013;24:1802-1807.
  21. Sella A, Sella T, Peer A, et al. Activity of cabazitaxel after docetaxel and abiraterone acetate therapy in patients with castration-resistant prostate cancer. Clin Genitourin Cancer. 2014;12:428-432.
  22. Nakouzi NA, Moulec SL, Albigès L, et al. Cabazitaxel remains active in patients progressing after docetaxel followed by novel androgen receptor pathway targeted therapies [published online ahead of print May 2, 2014]. Eur Urol. 2015;68:228-235.
  23. Madan R, Dahut WL. Abiraterone’s efficacy confirmed; time to aim higher. Lancet Oncol. 2015;16:119-121.
  24. El-Amm J, Aragon-Ching JB. The changing landscape in the treatment of metastatic castration-resistant prostate cancer. Ther Adv Med Oncol. 2013;5:25-40.

25. Pinto A. Cabozantinib: a novel agent with dual mechanism of action for castration-resistant prostate carcinoma. Cancer Chemother Pharmacol. 2014;73:219-222.