Treatment/Prognosis

Question 1

What is the standard initial systemic therapy for metastatic prostate cancer?

Answer 1

ADT via surgical bilat orchiectomy, or more commonly through the use of a GnRH agonist, is the standard 1st-line therapy for metastatic prostate cancer. GnRH agonists act on the ant pituitary to cause a reduction in gonadal testosterone production to castrate levels.

Question 2

What is the pathophysiology of androgen deprivation in the Tx of prostate cancer?

Answer 2

Since the 1940s, testosterone has been implicated in the growth and survival of prostate cancer. Testosterone is converted to the potent dihydrotestosterone (DHT) in target tissues, and DHT binds with high affinity to the AR in prostate cancer cells. Upon translocation to the cancer cell nucleus, DHT-AR binds to DNA androgen response elements, thereby facilitating multiple prostate cancer growth pathways. Therefore, androgen deprivation can effectively inhibit these growth elements. (Huggins C et al., Cancer Res 1941)

Question 3

Is GnRH agonist therapy sup to orchiectomy for the Tx of metastatic prostate cancer?

Answer 3

Randomized trials and meta-analyses have confirmed equivalent long-term outcomes. Due to the irreversibility and psychological morbidity associated with surgical orchiectomy, GnRH agonists are generally the preferred approach for androgen deprivation. This therapy has primarily been shown to improve Dz progression and to reduce Dz-related complications. (MRC Prostate Cancer Group, Br J Urol 1997; Wilt T et al., Cochrane Review 2004; Vogelzang NJ et al., Urology 1995)

Question 4

What are 3 commonly used GnRH agonists?

Answer 4

The most commonly used GnRH agonists include:

Goserelin (Zoladex)
Leuprolide (Lupron)
Triptorelin (Trelstar)

All 3 are available as depot formulations. These different GnRH agonist formulations are considered to be equally efficacious.

Question 5

What other modalities of androgen suppression are available?

Answer 5

GnRH antagonists (degarelix) achieve fast declines in testosterone to castrate levels and are not associated with a testosterone flare response. Antiandrogens (AAs), which are nonsteroidal competitive androgen receptor (AR) antagonists (including bicalutamide, flutamide, or nilutamide) block the peripheral effects of gonadal and extragonadal (adrenal) androgens. (Klotz L et al., BJU Int 2008)

Question 6

Should ADT be initiated for biochemical recurrence after definitive RT in the absence of clinically evident mets?

Answer 6

The data are mixed, and the answer is therefore controversial. Although the effects on distant metastatic risk remain unclear, available data suggest that early initiation of ADT may be particularly beneficial for high-risk cancers (GS >7 and rapid PSA-DT). (Faria SL et al., Urology 2006; Walsh PC et al., J Urol 2001)

Question 7

Should ADT be initiated for radiographically evident but asymptomatic mets?

Answer 7

In general, yes. Although ADT is not curative and primarily administered with palliative intent in the metastatic setting, studies have shown significantly improved PFS and reduced Dz-related complications with early initiation of ADT when c/w therapy deferred until signs and Sx of clinical progression. (MRC Prostate Cancer Group, Br J Urol 1997; Wilt T et al., Cochrane Review 2004)

Question 8

Is intermittent ADT as efficacious as continuous ADT for metastatic Dz?

Answer 8

No. Continuous ADT is considered the standard of care for treating metastatic Dz. The premise behind the use of intermittent ADT is to potentially help reduce side effects, cost, and progression to castration-resistant Dz. However; the Intergroup 0162 randomized phase III trial was unable to demonstrate that intermittent therapy was noninf to continuous therapy with respect to survival. However, in men with PSA-only recurrence following definitive RT, intermittent ADT is noninf to continuous ADT. (Hussain M et al., NEJM 2013; Crook JM et al., NEJM 2012)

Question 9

Can AAs be used as monotherapy for metastatic Dz?

Answer 9

No. The available evidence does not support the routine use of AA monotherapy for metastatic Dz. Randomized studies demonstrated inf outcomes with standard low-dose bicalutamide when compared to castration therapy. In addition, a meta-analysis of several trials showed a trend toward OS benefit with medical/surgical castration compared to nonsteroidal AA therapy. As a result, common practice involves use of either a GnRH agonist alone or in combination with a nonsteroidal AA (and not AA monotherapy). (Bales GT et al., Urology 1996; Kaisary AV et al., Eur Urol 1995; Seidenfeld J et al., Ann Int Med 2000)

Question 10

Should GnRH analogs be used alone or in combination with AAs (combined androgen blockade [CAB])?

Answer 10

Possibly. Several randomized trials and meta-analyses have shown a small but significant OS benefit with CAB relative to ADT monotherapy. However, the potential benefit of CAB must be balanced with potential increased toxicity in an individual pt. Of note, GnRH monotherapy may cause an initial flare of testosterone and Dz-related Sx, which can be prevented by preceding therapy with a short course of AAs. (PCTCG, Lancet 2000; Samson DJ et al., Cancer 2002; Kuhn JM et al., NEJM 1989)

Question 11

What is the anticipated median OS for pts with metastatic castration-sensitive prostate cancer initiating Tx with ADT?

Answer 11

The median OS in men with metastatic prostate cancer initiating ADT is appx 4–5 yrs, depending on the level of Dz burden. (Hussain M et al., NEJM 2013; Sweeney CJ et al., NEJM 2015; James ND et al., Lancet 2016)

Question 12

Is there a role for chemo in the Tx of castration-sensitive metastatic prostate cancer?

Answer 12

Yes. The randomized phase III CHAARTED and STAMPEDE clinical trials demonstrated a significant improvement in OS with the addition of 6 Tx of docetaxel chemo to standard ADT. In the CHAARTED study, this clinical benefit was most pronounced in pts presenting with a “high-burden” of metastatic Dz, as defined by the presence of visceral mets and/or high-volume osseous mets. (Sweeney CJ et al., NEJM 2015; James ND et al., Lancet 2016)

Question 13

Typically, how long after initiating ADT does it take before a pt’s prostate cancer becomes castration-resistant?

Answer 13

Castration-resistance usually occurs within 18–24 mos of starting ADT. (Eisenberger MA et al., NEJM 1998, Sweeney CJ et al., NEJM 2015)

Question 14

What are the commonly used initial management strategies for pts with new progression to castration-resistant prostate cancer?

Answer 14

If CAB is being administered, withdrawal of the AA may result in a temporary PSA decline. If a GnRH analog alone is being given, the addition of an AA may help.

Question 15

What are the 6 systemic therapy options that have demonstrated an OS benefit in metastatic castration-resistant Dz?

Answer 15

The 6 systemic Tx are:

1. Abiraterone (Zytiga)
2. Enzalutamide (Xtandi)
3. Docetaxel (Taxotere)
4. Cabazitaxel (Jevtana)
5. Sipuleucel-T (Provenge)
6. Radium-223 (Xofigo)

Question 16

What are the next-generation hormonal therapy options for pts with castration-resistant prostate cancer?

Answer 16

Abiraterone is an oral inhibitor of the 17α hydroxylase and the 17,20 lyase enzymes in the adrenal androgen synthetic pathway. Enzalutamide is an oral AR antagonist that additionally reduces AR nuclear translocation and DNA binding. Both abiraterone and enzalutamide have demonstrated OS improvements in pts with metastatic castration-resistant Dz, either before or after docetaxel chemo. (de Bono JS et al., NEJM 2011; Ryan CJ et al., NEJM 2013; Scher HI et al., NEJM 2012; Beer TM et al., NEJM 2014)

Question 17

What chemo options are available to pts with metastatic castration-resistant Dz?

Answer 17

Docetaxel is the standard initial chemo based on efficacy demonstrated in 2 randomized trials: TAX 327 and SWOG 9916 (Tannock IF et al., NEJM 2004; Petrylak DP et al., NEJM 2004). The taxane cabazitaxel is considered the preferred 2nd-line chemotherapeutic agent for pts with castration-resistant prostate cancer. Cabazitaxel/prednisone has been shown to improve OS in pts who have progressed following docetaxel in a phase III randomized trial. (de Bono JS et al., Lancet 2010)

Question 18

What radiopharmaceutical is available for pts with symptomatic bone mets from castration-resistant prostate cancer, and what is its mechanism of action?

Answer 18

Radium-223 is approved for use in pts with symptomatic bone mets and no visceral mets. In the randomized phase III ALSYMPCA trial, radium-223 demonstrated improvement in OS and reduced skeletal-related events (Parker C et al., NEJM 2013). Radium-223 is the first α-particle emitter to be approved for routine clinical practice. The short range and high RBE of the α-particles produced by radium-223 theoretically result in more rapid cell killing and less marrow toxicity when c/w previously tested β-emitters, such as strontium-89 and samarium-153.

Question 19

What immunotherapy is available to pts with asymptomatic or minimally symptomatic metastatic castration-resistant Dz?

Answer 19

For pts who are asymptomatic or minimally symptomatic, sipuleucel-T is considered an appropriate therapy. Sipuleucel-T, an autologous active cellular immunotherapy, demonstrated improvement in OS in a phase III randomized trial. (Kantoff PW et al., NEJM 2010)

Question 20

What additional therapy should be offered to pts with castrate-resistant prostate cancer and clinically detectable bone mets?

Answer 20

Denosumab or zoledronic acid, which have been shown in randomized trials to improve bone mineral density and decrease the risk of fracture. Palliative focal radiotherapy may also be considered, as appropriate. (Michaelson MD et al., JCO 2007; Smith MR et al., NEJM 2009)