Metastatic prostate cancer

Question 1

What % of newly diagnosed prostate cancer pts present with locally advanced or metastatic Dz?

Answer 1

Appx 10%–20% of pts will present with at least locally advanced Dz.

Question 2

Has the incidence of metastatic prostate cancer changed with the introduction of the PSA?

Answer 2

Yes. The introduction of the PSA into general practice in the early 1990s appears to have decreased the incidence of metastatic prostate cancer; a SEER database analysis showed a 52% decrease in the incidence of metastatic prostate cancer Dx from 1990 to 1994. (Stephenson RA et al.,World J Urol 1997)

Question 3

How are most cases of metastatic prostate cancer identified?

Answer 3

The majority of metastatic prostate cancer cases are identified by an isolated biochemical (PSA-only) recurrence; a much smaller proportion of cases are
detected by signs/Sx of metastatic Dz (pain, pathologic fracture, weight loss, anemia, SC compression, etc.). (Lee WR et al., JCO 1997; D’Amico AV et al., JNCI 2003)

Question 4

What is the anticipated natural Hx of prostate cancer after biochemical failure following local therapy?

Answer 4

Following local therapy and subsequent biochemical failure, the median time to development of mets is 8 yrs, and the median time to death is 13 yrs. (Pound CR et al., JAMA 1999; Freedland SJ et al., JAMA 2005)

Question 5

What are common predictors of a poorer prognosis after biochemical failure following local therapy?

Answer 5

Poor prognostic factors after biochemical failure following local therapy include: (D’Amico AV et al., JNCI 2003; Stephenson RA et al., JAMA 2004; Zhou P et al., JCO 2005; Horwitz EM et al., IJROBP 2008)

1. PSA-DT <3 mos
2. GS ≥8
3. T3b Dz
4. LN involvement
5. Short time to biochemical failure following local therapy (<3 yrs)

Question 6

What is the most common site of prostate cancer mets?

Answer 6

The most common site is the axial skeleton, including the pelvis, vertebral column, ribs, and proximal long bones. Indeed, >80% of pts who die from prostate cancer have bony mets at autopsy. These lesions are usually osteoblastic, but may be lytic as well.

Question 7

What imaging modalities are commonly used for a metastatic workup?

Answer 7

The imaging modalities most commonly used for workup of suspected metastatic prostate cancer include whole body bone scan (technetium-99m bone scintigraphy), CT abdomen/pelvis with contrast, and chest imaging with
a CXR or CT. X-ray radiographs or MRI should be used if bone scan findings are equivocal.

Question 8

How sensitive are bone scans and CT scans for the detection of mets following biochemical failure?

Answer 8

Bone scan and CT scan are rarely positive until PSA values exceed 30 ng/mL in the absence of prior ADT. These scans are also more likely to be positive with faster PSA velocities. (Cher ML et al., J Urol 1998; Kane CJ et al., Urology 2003)

Question 9

Is there a role for PET scans in the evaluation of metastatic prostate cancer?

Answer 9

PET imaging is an evolving diagnostic tool, and multiple PET modalities are currently under investigation. Fluciclovine (18F-FACBC) was recently approved by the FDA for the detection of recurrent prostate cancer in men with rising PSA following Sg or RT. Optimal test characteristics are observed at higher PSA values. Multiple prostate specific membrane antigen (PSMA)
targeting PET agents (such as 68Ga-PSMA) are also currently under investigation and may enter routine prostate cancer evaluation in the future.

Question 10

Is there a role for prostate Bx after biochemical failure in pts initially treated with RT?

Answer 10

Based on an ASTRO consensus statement, prostate re-Bx should be considered if the pt is considering additional local (salvage) therapy and is >2 yrs after the completion of RT. (Cox JD et al., JCO 1999)

Question 11

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

Answer 11

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 12

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

Answer 12

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 13

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

Answer 13

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.

Question 14

What are 3 commonly used GnRH agonists?

Answer 14

1. Goserelin (Zoladex)
2. Leuprolide (Lupron)
3. Triptorelin (Trelstar)

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

Question 15

What other modalities of androgen suppression are available?

Answer 15

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 16

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

Answer 16

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 17

Should ADT be initiated for radiographically evident but asymptomatic mets?

Answer 17

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 18

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

Answer 18

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 castrationresistant
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 19

Can AAs be used as monotherapy for metastatic Dz?

Answer 19

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 20

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

Answer 20

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 21

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

Answer 21

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 22

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

Answer 22

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 highvolume osseous mets. (Sweeney CJ et al., NEJM 2015; James ND et al., Lancet 2016)

Question 23

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

Answer 23

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

Question 24

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

Answer 24

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 25

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

Answer 25

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 26

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

Answer 26

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 27

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

Answer 27

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 28

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

Answer 28

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 29

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

Answer 29

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 30

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

Answer 30

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)

Question 31

What are the common side effects of ADT?

Answer 31

Side effects of ADT include: hot flashes, decreased libido, fatigue, gynecomastia, anemia, decreased muscle mass, decreased bone mineral density, obesity, mood changes, dyslipidemia, insulin resistance, and possible
increased risks for diabetes, coronary artery Dz, and cognitive effects. (Higano CS, Urology 2003; Keating NL et al., JCO 2006)

Question 32

What are the common side effects of AA therapy?

Answer 32

Common side effects of bicalutamide, the most commonly prescribed AA d/t its favorable toxicity profile, include breast tenderness and gynecomastia, decreased libido, diarrhea, and potential hepatotoxicity.