Review Article
`
`Abbreviations
`and Acronyms
`ADT ¼ androgen deprivation
`therapy
`AE ¼ adverse event
`AR ¼ androgen receptor
`AR-V ¼ AR splice variant
`COU-AA-302 ¼ Abiraterone
`Acetate in Asymptomatic or
`Mildly Symptomatic Patients with
`mCRPC
`CTC ¼ circulating tumor cell
`CYP17 ¼ cytochrome P450 17
`FDA ¼ Food and Drug
`Administration
`mCRPC ¼ metastatic castration
`resistant prostate cancer
`OS ¼ overall survival
`PFS ¼ progression-free survival
`PREVAIL ¼ Safety and Efficacy
`Study of Oral MDV3100 in
`Chemotherapy-Naive Patients
`with Progressive Metastatic
`Prostate Cancer
`PSA ¼ prostate-specific antigen
`QoL ¼ quality of life
`rPFS ¼ radiographic progression-
`free survival
`
`Treating Patients with Metastatic Castration Resistant
`Prostate Cancer: A Comprehensive Review of
`Available Therapies
`
`E. David Crawford,*,† Celestia S. Higano,‡ Neal D. Shore,§
`Maha Hussaink and Daniel P. Petrylak{
`
`From the Department of Urologic Oncology, School of Medicine, University of Colorado Denver (EDC), Aurora,
`Colorado, Division of Medical Oncology, Department of Medicine and Department of Urology, School of Medicine,
`University of Washington and Fred Hutchinson Cancer Research Center, Seattle (CSH), Washington,
`Carolina Urologic Research Center (NDS), Myrtle Beach, South Carolina, University of Michigan Comprehensive
`Cancer Center (MH), Ann Arbor, Michigan, and Smilow Cancer Center, Yale University (DPP), New Haven, Connecticut
`
`Purpose: The availability of newly approved treatment options for metastatic
`castration resistant prostate cancer is not matched with conclusive data on
`optimal sequencing strategies and resistance patterns. A comprehensive review
`of efficacy and safety data for new agents and current knowledge regarding
`treatment sequencing would enable treating physicians to make rational drug
`selections in patients with metastatic castration resistant prostate cancer.
`Materials and Methods: We searched MEDLINEÒ and relevant congresses for
`data on cabazitaxel, docetaxel, 223radium dichloride, abiraterone, enzalutamide
`and sipuleucel-T, focusing on sequencing strategies, resistance mechanisms and
`biomarkers of response.
`Results: Abiraterone and enzalutamide target the androgen axis with different
`mechanisms of action. Abiraterone blocks cytochrome P450 17,
`inhibiting
`androgen synthesis, whereas enzalutamide inhibits androgen receptor, reducing
`nuclear translocation of
`the androgen receptor complex and subsequent
`DNA binding. Both agents provide improved overall survival in patients with
`metastatic castration resistant prostate cancer who received prior docetaxel
`treatment and in those who are chemotherapy na€ıve. Cabazitaxel provides
`improved overall survival in patients with metastatic castration resistant pros-
`tate cancer with prior docetaxel therapy. Sipuleucel-T provides improved overall
`survival in asymptomatic patients and 223radium provides improved overall
`survival in chemotherapy na€ıve and chemotherapy treated patients with symp-
`tomatic bone metastases. Selecting the correct treatment with metastatic
`castration resistant prostate cancer is complex as no head-to-head trials have
`been done and comparison between existing trials is difficult due to differences in
`
`Accepted for publication June 21, 2015.
`* Correspondence: Department of Urologic Oncology, School of Medicine, University of Colorado, Denver, Mail Stop #F710, P.O. Box 6510,
`Aurora, Colorado 80045 (telephone: 720-848-0195; FAX: 720-848-0203; e-mail: edc@edavidcrawford.com).
`† Financial interest and/or other relationship with Bayer, MDx, Genomic Health, Janssen, Dendreon, Ferring, National Institutes of Health,
`University of Colorado Cancer Center and Ferring.
`‡ Financial interest and/or other relationship with Algeta, Amgen, Aragon, AstraZeneca, Bayer, Dendreon, Exelixis, Genentech, ImClone,
`Medivation, Millenium, Novartis, Oncogenex, Sanofi, Teva, CTI Pharma, AbbVie, BHR Pharma, Chiltern International, Pfizer, Johnson & Johnson
`and Orion.
`§ Financial interest and/or other relationship with Astellas, Bayer, Dendreon, Janssen, Ferring, Millenium, Medivation and Sanofi.
`k Financial interest and/or other relationship with Genentech, Medivation, Astellas and Johnson & Johnson.
`{ Financial interest and/or other relationship with Bayer, Bellicum, Dendreon, Sanofi Aventis, Johnson & Johnson, Exelixis, Ferring, Mil-
`lenium, Medivation, Pfizer, Oncogenix, Progenics and Celgene.
`
`0022-5347/15/1946-1537/0
`THE JOURNAL OF UROLOGY®
`Ó 2015 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
`
`http://dx.doi.org/10.1016/j.juro.2015.06.106
`Vol. 194, 1537-1547, December 2015
`
`Printed in U.S.A. www.jurology.com j 1537
`
`AVENTIS EXHIBIT 2054
`Mylan v. Aventis
`IPR2016-00627
`
`

`

`1538
`
`TREATING METASTATIC CASTRATION RESISTANT PROSTATE CANCER
`
`study populations and a lack of validated biomarkers. Factors to consider include prior therapy, symptom
`burden, metastasis type, performance status, comorbidities, adverse event profiles and patient preference.
`Another consideration is treatment sequence since some agents affect responses to subsequent choices. For
`example, resistance to abiraterone or enzalutamide may result in limited responses to subsequent androgen
`targeted agents. Identifying factors predictive of resistance is an area of ongoing research with androgen
`receptor variants representing a good candidate. Prognostic factors for survival are also likely to be useful and
`are currently being studied.
`Conclusions: New therapies for metastatic castration resistant prostate cancer have brought new
`challenges with regard to treatment selection and sequencing. While hormonal agents provide good
`therapeutic responses, resistance may be intrinsic without prior drug exposure. Identifying predictors of
`response and relevant biomarkers will allow therapies to be more precisely tailored to individual patient
`profiles.
`
`Key Words: prostatic neoplasms, neoplasm metastasis, castration,
`drug therapy, androgen antagonists
`
`FOR many years the mainstay of treatment for
`mCRPC was docetaxel. Since 2010, several treat-
`ments have shown a survival benefit in patients
`with mCRPC in phase 3 trials, leading to regulatory
`approval and subsequent inclusion in treatment
`guidelines (table 1).1
`Despite the numerous treatment options for
`mCRPC the impact on survival is less than optimal
`and there are limited data to provide guidance
`regarding how to optimally sequence approved
`treatments for individual patients. Recently results
`from several studies of mCRPC began to identify
`clinical factors that predict benefit from androgen
`axis targeted and other therapies, which might
`help inform treatment decisions for individual pa-
`tients. This article provides an overview of phase 3
`trial data for androgen axis targeting agents in
`mCRPC as well as perspectives on other recently
`approved mCRPC agents, a review of studies
`attempting to assess the impact of resistance to
`androgen axis targeting agents and emerging data
`on prognostic factors and biomarkers in patients
`with mCRPC.
`
`METASTATIC CASTRATION RESISTANT
`PROSTATE CANCER TREATMENT
`EVOLUTION
`The benefits of recently approved treatments for
`mCRPC have been shown in 7 randomized phase 3
`trials (table 2).
`
`Trials of Androgen Axis Targeting Agents
`After Chemotherapy. Abiraterone and enzalutamide
`target
`the androgen axis. Abiraterone inhibits
`androgen synthesis by the adrenal glands and
`testes, and within the prostate tumor by blocking
`CYP17, a critical enzyme in testosterone synthesis.2
`
`including
`
`In contrast, enzalutamide targets AR,
`intracellular signaling functions.3
`The efficacy of abiraterone and enzalutamide in
`mCRPC was proved initially in men who had
`received prior docetaxel chemotherapy.
`In the
`abiraterone trial 1,195 patients received prednisone
`5 mg twice daily in combination with oral abirater-
`one 1,000 mg once daily or placebo.2,4 In the enza-
`lutamide
`trial
`1,199
`patients
`received
`oral
`enzalutamide 160 mg daily or placebo.3 After
`20.2 months of median followup in the abiraterone
`trial OS was longer for abiraterone/prednisone vs
`placebo/prednisone (median 15.8 vs 11.2 months,
`p <0.001).4 In the enzalutamide trial, which was
`reported with shorter
`followup (median 14.4
`months), OS was also longer for enzalutamide vs
`placebo (median 18.4 vs 13.6 months, p <0.001).3
`For both agents superiority vs the control arm was
`demonstrated for other end points, including stan-
`dard assessments
`(PSA response rate,
`tumor
`response, time to PSA progression and rPFS) as well
`as other end points (time to skeletal events, pain
`palliation and health related QoL).2e6
`AEs that were more frequent for abiraterone/
`prednisone vs placebo/prednisone included urinary
`tract infection in 12% vs 7% of patients (p ¼ 0.02),
`fluid retention/edema in 31% vs 22% (p ¼ 0.04) and
`hypokalemia in 17% vs 8% (p <0.001) with the
`latter 2 AEs attributable to mineralocorticoid excess
`resulting from CYP17 blockade.2 AEs that appeared
`more frequent for enzalutamide vs placebo treat-
`ment included fatigue in 34% vs 29% of cases,
`diarrhea in 21% vs 18%, hot flashes in 20% vs 10%,
`musculoskeletal pain in 14% vs 10%, headache in
`12% vs 6%, hypertension in 7% vs 3% and seizures
`in 0.6% vs 0%.3
`Overall each trial provided confirmation that
`mCRPC remains in part an androgen driven disease
`
`

`

`TREATING METASTATIC CASTRATION RESISTANT PROSTATE CANCER
`
`1539
`
`Table 1. FDA approved anticancer treatments for mCRPC, excluding treatments specifically for bone metastases
`
`Mechanism
`
`Indication
`
`Dose
`
`Initial FDA mCRPC
`Approval Date
`
`Treatment
`Docetaxel (TaxotereÒ)*
`
`Sipuleucel-T (ProvengeÒ)
`
`Taxane chemotherapy
`(microtubule inhibitor)
`Autologous cellular
`immunotherapy
`
`mCRPC
`
`Asymptomatic or minimally
`symptomatic mCRPC
`
`Cabazitaxel (JevtanaÒ)*
`
`Abiraterone acetate (ZytigaÒ)*
`
`Enzalutamide (XtandiÒ)
`223Radium dichloride (XofigoÒ)
`
`Taxane chemotherapy
`(microtubule inhibitor)
`CYP17 (androgen synthesis)
`inhibitor
`AR inhibitor
`a Particle emitting
`radiopharmaceutical
`
`* Combination agent oral prednisone 10 mg daily.
`
`75 mg/m2 Intravenously every
`3 weeks
`250 ml Infusion containing
`50 million or greater autologous
`activated CD54þ cells, every
`2 weeks, 3 doses
`25 mg/m2 Intravenously every
`3 weeks
`1000 mg Orally once daily
`
`mCRPC with previous docetaxel
`treatment
`mCRPC
`
`mCRPC
`mCRPC with symptomatic bone
`metastases þ no known visceral
`metastatic disease
`
`160 mg Orally once daily
`50 kBq (1.35 mCi)/kg body wt
`intravenously every 4 weeks,
`6 doses
`
`5/04
`
`4/10
`
`6/10
`
`4/11
`
`9/12
`5/13
`
`even after progression on chemotherapy and that
`androgen blockade through different mechanisms
`can lead to improved patient outcomes.2,3
`
`In Chemotherapy Na€ıve Patients. The clinical benefits
`of abiraterone and enzalutamide have also been
`shown in trials of men with asymptomatic or
`na€ıve
`minimally
`symptomatic,
`chemotherapy
`mCRPC.
`In the COU-AA-302 abiraterone trial
`1,088 patients received oral abiraterone 1,000 mg
`daily plus prednisone 5 mg twice daily or placebo
`plus prednisone.7,8 In the PREVAIL enzalutamide
`trial 1,717 patients received oral enzalutamide
`160 mg daily or placebo.9 In both trials co-primary
`end points were OS and rPFS. Notably the
`trials differed in inclusion criteria with visceral
`metastases permitted in the enzalutamide trial
`but not in the abiraterone trial.7e9 After a median
`49.4-month followup abiraterone/prednisone vs
`placebo/prednisone resulted in longer median OS
`(34.7 vs 30.3 months, p ¼ 0.0027), representing a
`20% risk reduction.10 With enzalutamide rPFS data
`were reported after 12-month followup and showed
`superiority for enzalutamide vs placebo (median not
`reached vs 3.9 months, p <0.001) with an 81% risk
`reduction. OS findings from PREVAIL, analyzed at
`a median followup of 26 months, also showed
`superiority for enzalutamide vs placebo (median not
`reached vs 31.0 months, p <0.001) with a 27% risk
`reduction.9 In an earlier interim analysis median
`OS had been estimated as 32.4 months
`for
`enzalutamide vs 30.2 months for placebo. Notably a
`survival advantage for enzalutamide vs placebo
`was observed in patients with visceral disease.
`Abiraterone and enzalutamide showed benefits vs
`placebo in other end points, including higher rates
`of PSA response and tumor response, longer time
`to PSA progression or initiation of chemotherapy
`and delayed deterioration of patient
`reported
`QoL/functional status. The trials differed in other
`
`reported.
`points
`end
`secondary/exploratory
`Abiraterone delayed several pain related end points
`and enzalutamide delayed skeletal related events.7e9
`In COU-AA-302 AEs
`that appeared more
`frequent for abiraterone plus prednisone vs placebo
`plus prednisone included fatigue in 40% vs 35% of
`patients, arthralgia in 29% vs 24%, peripheral
`edema in 26% vs 21%, hot flush in 23% vs 18%,
`diarrhea in 23% vs 18%, hypertension in 22% vs
`14% and liver enzyme increases (grade 3/4 alanine
`aminotransferase or aspartate aminotransferase
`increase) in 3% to 6% vs 1%.8 In PREVAIL AEs that
`appeared to be more frequent for enzalutamide vs
`placebo included fatigue in 36% vs 26% of patients,
`back pain in 27% vs 22%, constipation in 22% vs
`17%, hot flush in 18% vs 8%, hypertension in 13% vs
`4% (grade 3/4 in 7% vs 2%), asthenia in 13% vs 8%
`and falls in 12% vs 5%.9
`Overall these trials demonstrated that androgen
`axis targeted agents can also provide clinical
`benefits to men with asymptomatic or minimally
`symptomatic mCRPC who have not
`received
`chemotherapy.
`
`Recent Trials of Nonhormonal Agents in
`Metastatic Castration Resistant Prostate Cancer
`Other randomized phase 3 trials have shown that
`other nondocetaxel agents could extend survival or
`provide benefit in patients with mCRPC (table 2).
`Sipuleucel-T is a therapeutic cancer vaccine
`prepared by extracting peripheral blood mono-
`nuclear cells from the individual patient via leuka-
`pheresis. The cells are shipped to a manufacturing
`facility, where antigen presenting cells are cultured
`ex vivo with PA2024 recombinant fusion protein
`(prostatic acid phosphatase fused to granulocyte-
`macrophage
`colony-stimulating
`factor). After
`approximately 40 hours the cells are washed,
`resuspended and shipped back to the clinic provided
`
`

`

`1540
`
`TREATING METASTATIC CASTRATION RESISTANT PROSTATE CANCER
`
`Table 2. Baseline characteristics and findings of recent mCRPC phase 3 trials
`
`Pre-chemotherapy Trials
`
`Post-Docetaxel Trials
`
`Bone Metastatic,
`Nonvisceral
`
`IMPACT*,11
`
`COU-AA-302*,7,8
`
`PREVAIL9
`
`TROPIC12
`
`COU-AA-301†,2,4
`
`AFFIRM‡,3,43
`
`ALSYMPCA13
`
`Arm:
`Experimental
`(No. pts)
`Control
`
`Age:
`Median age
`% 75 or Greater
`% Performance score:
`0e1
`2 or Greater
`% Metastases:
`Bone
`Visceral
`% Prior docetaxel
`Median baseline
`PSA (ng/ml)
`
`Sipuleucel-T (341)
`
`Placebo
`
`Abiraterone/prednisone
`(546)
`Prednisone
`
`Enzalutamide (872)
`
`Placebo
`
`Cabazitaxel/prednisone
`(378)
`Mitoxantrone/prednisone
`
`Abiraterone/prednisone
`(797)
`Prednisone
`
`Enzalutamide
`(800)
`Placebo
`
`223Radium þ best
`supportive care (614)
`Placebo þ best
`supportive care
`
`72
`Not reported
`
`100
`0
`
`93
`0
`16
`51.7
`
`71
`34
`
`100
`0
`
`83
`0
`0
`42.0
`
`Baseline characteristics
`
`72
`36
`
`100
`0
`
`85
`11
`0
`54.1
`
`68
`18
`
`93
`7
`
`80
`25
`100
`143.9
`
`69
`28
`
`90
`10
`
`89
`32
`100
`128.8
`
`69
`25
`
`91
`9
`
`92
`27
`100
`107.7
`
`71
`28
`
`87
`13
`
`100
`0
`57
`146
`
`Median mos survival
`(improvement over
`comparator arm)
`
`OS 25.8 (4.1), time to
`objective progression
`3.7 (0.1)
`
`OS 35.3 (5.2),
`rPFS 16.5 (8.3)
`
`% Most frequent AEs:
`Any grade hematological
`þ nonhematological
`(25% or greater)
`
`Chills (54), fatigue (39),
`back pain (34),
`pyrexia (29), nausea (28)
`
`Fatigue (40), back pain (33),
`arthralgia (29), fluid
`retention (29), peripheral
`edema (26)
`
`Results
`
`Interim OS 32.4 (2.2), median
`rPFS not reached vs 3.9 in
`comparator arm (1-yr rPFS
`65% for 51% improvement)
`
`Fatigue (36), back pain (27)
`
`Grade 3 or greater
`(5% or greater)
`
`Not applicable
`
`Cardiac disorders (7),
`alanine aminotransferase
`increased (6)
`
`Hypertension (7)
`
`OS 15.1 (2.4),
`PFS 2.8 (1.4)
`
`OS 15.8 (4.6),
`rPFS 5.6 (2.0)
`
`OS 18.4 (4.8),
`rPFS 8.3 (5.4)
`
`OS 14.9 (3.6), for PFS,
`rPFS þ time to objective
`progression no imaging
`on trial
`
`Anemia (97),§ leukopenia
`(96),§ neutropenia (94),§
`thrombocytopenia (47),§
`diarrhea (47), fatigue (37),
`nausea (34)
`
`Neutropenia (82),§
`leukopenia (68),§ anemia
`(11),§ febrile neutropenia (8),§
`diarrhea (6), fatigue (5),
`asthenia (5)
`
`Fatigue (47), fluid
`retention/edema (33),
`back pain (33),
`nausea (33),
`arthralgia (30),
`constipation (28),
`bone pain (27)
`Fatigue (9), anemia (8),
`back pain (7),
`bone pain (6),
`arthralgia (5),
`cardiac disorders (5)
`
`Fatigue (34),
`back pain (26)
`
`Bone pain (50), diarrhea (25),
`anemia (31), nausea (36),
`fatigue (26)
`
`Fatigue (6),
`back pain (5)
`
`Bone pain (21), anemia (13),
`thrombocytopenia (7)
`
`* Trial excluded patients with liver metastases or ECOG (Eastern Cooperative Oncology Group) performance score 2 or greater.
`† Abiraterone Acetate in Castration-Resistant Prostate Cancer Previously Treated with Docetaxel-Based Chemotherapy.
`‡ Safety and Efficacy Study of MDV3100 in Patients with Castration-Resistant Prostate Cancer Who Have Been Previously Treated with Docetaxel-Based Chemotherapy.
`§ Hematological data based on laboratory assessments.
`
`

`

`TREATING METASTATIC CASTRATION RESISTANT PROSTATE CANCER
`
`1541
`
`that release specifications are met. Sipuleucel-T is
`then infused in a manner similar to any blood
`product. This procedure is repeated every 2 weeks
`for a total of 3 infusions.11 In the phase 3 IMPACT
`(ProvengeÒ [Sipuleucel-T] Active Cellular Immu-
`notherapy Treatment of Metastatic Prostate Cancer
`After Failing Hormone Therapy) trial men with
`asymptomatic mCRPC,
`including approximately
`20% who had received prior chemotherapy, were
`randomized to receive 3 infusions of sipuleucel-T or
`analogously prepared placebo containing only pe-
`ripheral blood mononuclear cells.11 Sipuleucel-T
`was associated with longer OS (median 25.8 vs
`21.7 months, p ¼ 0.03), although it had no effect on
`time to disease progression or PSA.11 AEs associ-
`ated with sipuleucel-T were mostly infusion related
`and transient. They occurred within 1 day after
`infusion and resolved 1 to 2 days later. More
`frequent AEs for sipuleucel-T vs placebo included
`chills in 54% vs 13% of patients, pyrexia in 29% vs
`14%, headache in 16% vs 5%, pain in 13% vs 7%,
`myalgia in 10% vs 5%, flu-like illness in 10% vs 4%,
`hypertension in 7% vs 3% and hyperhidrosis in 5%
`vs 1%.
`Cabazitaxel is a next generation taxane chemo-
`therapy developed to overcome resistance to doce-
`taxel treatment. In the TROPIC (XRP6258 Plus
`Prednisone Compared to Mitoxantrone Plus Pred-
`nisone in Hormone Refractory Metastatic Prostate
`Cancer) trial men with mCRPC that had progressed
`after docetaxel
`treatment received intravenous
`cabazitaxel 25 mg/m2 or mitoxantrone 12 mg/m2
`every 3 weeks for up to 10 cycles, each in combina-
`tion with prednisone 10 mg daily.12 Compared with
`mitoxantrone, cabazitaxel treatment resulted in
`longer median OS (15.1 vs 12.7 months) and PFS
`(2.8 vs 1.4 months, each p <0.0001), significantly
`higher rates of PSA and tumor response, and longer
`time to PSA progression. AEs associated with cab-
`azitaxel were characteristic of taxanes. The most
`frequent AEs were hematological, including grade 3
`or greater neutropenia (82% of cases with cab-
`azitaxel vs 58% with mitoxantrone) and leukopenia
`(68% vs 42%). Grade 3 or greater febrile neu-
`tropenia with cabazitaxel vs mitoxantrone devel-
`oped in 8% vs 1% of cases. The most frequent
`nonhematological AEs of any grade for cabazitaxel
`vs mitoxantrone included gastrointestinal distur-
`bances such as diarrhea in 47% vs 11% of patients,
`nausea in 34% vs 23% and vomiting in 23% vs 10%,
`fatigue in 37% vs 27% and peripheral neuropathy in
`14% vs 3%.
`More recently phase 3 data were reported for
`223radium, an a emitting radiopharmaceutical agent
`that accumulates preferentially in bone metastases.
`The ALSYMPCA (A Phase III Study of Radium-223
`Dichloride in Patients with Symptomatic Hormone
`
`Refractory Prostate Cancer with Skeletal Metasta-
`ses) trial in 921 men included those with castration
`resistant prostate cancer metastatic to bone (2 or
`more sites) with pain (evidenced by regular use of
`analgesic medication or external beam radiation
`therapy for cancer related bone pain within the
`previous 12 weeks) with no known visceral metas-
`tases.13 Patients had received or were ineligible for/
`unable/unwilling to receive docetaxel. They were
`randomized to 6 cycles of intravenous 223radium or
`placebo every 4 weeks, each in combination with
`best standard of care. This was the routine care
`provided at each center, such as local external beam
`radiation therapy or glucocorticoid, antiandrogen,
`ketoconazole or estrogen treatment. Chemotherapy,
`hemibody external radiotherapy and other systemic
`radionuclides were not permitted. The study was
`stopped after a positive interim analysis. OS was
`longer for 223radium vs placebo (median 14.9 vs
`11.3 months, p <0.001) as was time to first symp-
`tomatic skeletal event and time to elevation in PSA
`or alkaline phosphatase. A higher proportion of pa-
`tients treated with 223radium had an improvement in
`QoL. Post hoc analyses showed that 223radium
`reduced pain scores and opioid use compared with
`placebo.14 Rates of AEs of all grades, or grade 3 or
`greater were lower in the 223radium arm vs the pla-
`cebo arm. Rates of grade 3 or greater hematological
`AEs included anemia in 13% vs 13% cases, throm-
`bocytopenia in 7% vs 2% and neutropenia in 2% vs
`1%. Of the frequent nonhematological AEs of all
`grades, only diarrhea in 25% vs 15% of patients,
`vomiting in 18% vs 14% and peripheral edema in 13%
`vs 10% seemed more frequent with 223radium
`whereas bone pain (50% vs 62%) was less frequent
`and other AEs had similar rates.13
`
`POTENTIAL LIMITATIONS IN APPLYING
`PHASE 3 TRIAL FINDINGS TO
`CONTEMPORARY CLINICAL PRACTICE
`Exposure to docetaxel has been used as a convenient
`but artificial disease setting leading to compart-
`mentalization of subsequently approved agents into
`pre-docetaxel and post-docetaxel roles. The dearth of
`active agents to use as comparators in clinical trials
`resulted in a low bar so that all nonchemotherapy
`trials tested new agents against placebo or placebo
`plus prednisone. Therefore, although several options
`are effective treatments for mCRPC, each treatment
`with a different toxicity profile, it is difficult to assess
`the comparative effectiveness of treatments when
`there is a paucity of head-to-head comparator trials.
`Currently there are no data to indicate whether one
`treatment is more effective than another. Cross-trial
`comparisons are hampered by variations in available
`treatments based on the era in which the trial was
`
`

`

`1542
`
`TREATING METASTATIC CASTRATION RESISTANT PROSTATE CANCER
`
`performed and on global differences in approvals for
`agents. Furthermore, docetaxel history, control
`arms, concurrent treatment and eligibility/exclusion
`criteria relating to symptom burden or metastatic
`sites differ among trials. In addition, because the
`treatment landscape has evolved rapidly since these
`trials were performed, current patients will now
`have received different treatments before and after
`docetaxel, and subsequently have different clinical
`histories than those in the trials. Thus, it is unclear
`how the efficacy findings translate into current
`clinical practice.
`Another consideration is whether current thera-
`pies can be combined effectively and safely. For
`example, although 223radium was combined with
`best standard of care at the time in the confines of
`its phase 3 trial design, combining with chemo-
`therapy is not recommended1 (phase 1 trial
`in
`combination with docetaxel is ongoing). Also, data
`on combinations with newer agents,
`including
`enzalutamide and abiraterone, are lacking until
`results of ongoing combination phase 1/2 clinical
`trials are reported. However, evidence on novel
`combination strategies in early stages of the disease
`is emerging and may impact the treatment para-
`digm downstream.
`Recent data from the CHAARTED (Androgen
`Ablation Therapy with or without Chemotherapy in
`Treating Patients with Metastatic Prostate Cancer)
`trial are likely to have a major impact on patient
`care and therapy sequencing in patients with
`mCRPC. CHAARTED is a phase 3 trial evaluating
`the combination of docetaxel with ADT for castra-
`tion sensitive metastatic prostate cancer.15 A total
`of 790 patients were randomized to receive ADT
`plus docetaxel (75 mg/m2 every 3 weeks for 6 cycles)
`or ADT alone. Median OS was significantly longer
`for ADT plus docetaxel compared with ADT in the
`overall
`intent to treat population (57.6 vs 44.0
`months, p ¼ 0.0006) and in the subgroup of patients
`with high volume disease (49.2 vs 32.2 months, p ¼
`0.0012). Consistent with docetaxel
`toxicity in
`mCRPC grade 3/4 AEs included febrile neutropenia
`in 4% of patients, sensory neuropathy in 1% and
`motor neuropathy in 1%.
`Although the final study result has not yet been
`published,
`these data suggest
`that concurrent
`docetaxel and ADT are an appropriate consideration
`for patients with hormone
`sensitive disease,
`particularly those with high volume disease, thus,
`decreasing the proportion of patients in whom
`mCRPC develops and improving overall survival in
`patients who are chemotherapy na€ıve. These data
`suggest that chemohormonal combination therapy,
`particularly when given earlier in the disease, may
`offer improved outcomes compared with the more
`traditional
`sequenced monotherapy
`approach.
`
`Given the large number of agents now available,
`further trials examining these questions should be
`prioritized.
`
`SELECTING THERAPIES
`When patients are eligible for multiple treatments,
`the preferred strategy is to individualize the treat-
`ment plan by determining which treatment is most
`appropriate as initial therapy. Careful monitoring is
`performed so that resistance may be identified early
`and alternative options may be explored and
`implemented quickly to avoid missing a valuable
`therapeutic window of opportunity for more effec-
`tive treatment. Table 1 lists FDA approved in-
`dications of available treatments for mCRPC. For
`Ò
`initial
`treatment of mCRPC NCCN
`(National
`Comprehensive Cancer NetworkÒ) Clinical Practice
`Guidelines recommend abiraterone, enzalutamide,
`docetaxel
`(for
`rapidly
`progressing
`patients),
`sipuleucel-T (for patients with good performance
`level and at least a 6-month life expectancy),
`223radium (for patients with bone metastases and no
`visceral metastases) or participation in clinical tri-
`als.1 No consensus exists for the sequencing of
`therapies after failure of initial therapy or first line
`docetaxel. All listed agents plus cabazitaxel and
`salvage chemotherapy are options for second line
`therapy.1 AUA (American Urological Association)
`guidelines provide similar recommendations with
`the addition of ketoconazole plus steroid as a ther-
`apeutic option.16 Current guidelines and consensus
`statements for mCRPC provide a range of patient
`and disease factors that should be considered when
`selecting among available treatments, namely the
`existence of symptoms, type of metastases (bone/
`visceral), treatment history, response/speed of pro-
`gression on prior treatment (including ADT), per-
`formance status, preexisting toxicity/comorbidity,
`potential side effects of available therapies and pa-
`tient preferences.1,17,18 Given these parameters,
`patients are likely to receive a sequence of treat-
`ments. Therefore,
`it
`is important
`to consider
`whether the initial treatment choice may negatively
`affect the potential benefit of subsequent treat-
`ments, which may ultimately affect the order in
`which agents are prescribed and which therapy to
`suggest first. For example, cross-resistance among
`AR targeted agents is emerging, which may influ-
`ence treatment decisions.
`
`ANDROGEN AXIS TARGETING AGENTS
`(RESISTANCE AND IMPACT ON
`SUBSEQUENT TREATMENT)
`Various retrospective studies of mCRPC have
`investigated the impact of treatment resistance on
`
`

`

`TREATING METASTATIC CASTRATION RESISTANT PROSTATE CANCER
`
`1543
`
`the efficacy of subsequent agents. In studies in the
`post-docetaxel setting patients resistant to abir-
`aterone had modest responses to enzalutamide (50%
`or greater PSA decline in approximately 20% of
`patients and a median OS of 5 to 7 months)19,20 and
`vice versa (50% or greater PSA decline in 4% to 8%
`and a median OS 7.2 to 11.5 months).21,22 This
`suggests potential but incomplete cross-resistance.
`Since abiraterone was approved before enzaluta-
`mide, the majority of sequencing data available are
`in the post-abiraterone setting. One group reported
`that enzalutamide or docetaxel treatment after
`abiraterone had reduced efficacy (50% or greater
`PSA decline in 34% vs 40% of patients and a median
`PFS of 4.7 vs 4.4 months).23 Overall these studies
`suggest that subsequent treatments with either
`androgen targeted agent are less effective after
`enzalutamide and/or abiraterone. Furthermore,
`longer survival has been observed in post-docetaxel
`patients treated with abiraterone prior to cab-
`azitaxel rather than after cabazitaxel.24 Cabazitaxel
`appears to maintain activity in patients who have
`previously received docetaxel and abiraterone
`or enzalutamide, suggesting that the mechanism of
`action of cabazitaxel is mainly AR independent.25
`Prospective clinical studies are needed to com-
`pare efficacy findings with different
`treatment
`sequences.
`Development of resistance to androgen axis tar-
`geting agents has a potential negative impact on the
`effectiveness of
`follow-on therapies. In addition,
`decreasing resilience is observed in patients who
`have progressed on multiple lines of
`therapy.
`Therefore,
`identifying predictors of resistance to
`abiraterone
`or
`enzalutamide,
`such as AR-Vs
`(eg AR-V7), could help inform decisions about
`whether to choose a hormonal androgen axis targeting
`agent or chemotherapeutic strategy targeting AR in-
`dependent pathways in individual patients with
`mCRPC.
`
`PROGNOSTIC FACTORS FOR SURVIVAL IN
`PATIENTS TREATED WITH ANDROGEN AXIS
`TARGETING AGENTS AND OTHER AGENTS
`To investigate whether specific patient types derive
`a greater or lesser benefit from treatment with
`newer agents various subset analyses of phase 3
`trials have been performed. Across all trials the
`analyses of OS and/or rPFS in patient subgroups
`defined
`by
`standard
`baseline
`characteristics
`invariably showed that the experimental treatment
`was consistently superior to the control arm in
`different patient subsets.2e4,7e9,11e13 In addition,
`more detailed analyses of subgroups of specific in-
`terest have been reported, including those defined
`by the presence of visceral metastases,26 baseline
`
`serum androgen levels,27 duration of prior endo-
`crine therapy or baseline corticosteroid use for
`abiraterone after docetaxel, and older age, presence
`of visceral metastases, baseline PSA,28 or duration
`of prior hormone or docetaxel therapy29 for enzalu-
`tamide after docetaxel. In each case conclusions
`were consistent with overall trial findings.
`These data show that efficacy trends remain the
`same when individual characteristics are consid-
`ered. However, combining different baseline char-
`acteristics can identify profiles of patients with
`better or worse outcomes, ie those who might derive
`a greater or lesser benefit from treatment. The
`parameters identified can be used as prognostic
`factors for survival in patients with mCRPC.
`In particular several groups have attempted to
`define risk groups for patients receiving abirater-
`one. The Appendix shows a summary of recent
`findings using prognostic models in patients with
`mCRPC.
`In addition to baseline factors, early treatment
`effects also seem to be prognostic indicators of pa-
`tient outcomes, consistent with the age-old obser-
`vation that responders would be expected to achieve
`better outcomes than nonresponders. For example,
`PSA 4 ng/ml or less after 7 months of ADT has been
`shown to be a strong predictor of survival. Patients
`in whom PSA did not normalize (by achieving un-
`detectable PSA or PSA 4 ng/ml or less) after ADT
`had a poorer prognosis and lower survival rate.30 In
`this way PSA levels may provide a means of iden-
`tifying de novo resistant patients. Similar findings
`have been reported in the post-docetaxel setting.
`One group found significantly worse PFS and OS in
`patients in whom a 50% or greater PSA decline was
`not achieved during the first month of abiraterone
`or enzalutamide treatment.31
`Based on these analyses it appears that different
`prognostic models can be developed for different
`agents to assist with treatment selection, particu-
`larly if models predict different outcomes in the
`same patients. However, for any prognostic model
`full validation is needed before application to clin-
`ical practice. To date only 1 prognostic model has
`been validated and even then only partially.32
`Further studies are needed to determine whether
`prognostic models for patients considered at high
`risk for abiraterone (or enzalutami