Chemotherapy and novel therapeutics before radical prostatectomy for high-risk clinically localized prostate cancer

Urologic Oncology: Seminars and Original Investigations ] (2014) ∎∎∎–∎∎∎

Seminars article

Chemotherapy and novel therapeutics before radical prostatectomy for high-risk clinically localized prostate cancer Eugene K. Cha, M.D., James A. Eastham, M.D.* Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY Received 29 November 2014; accepted 1 December 2014

Abstract Although both surgery and radiation are potential curative options for men with clinically localized prostate cancer, a significant proportion of men with high-risk and locally advanced disease will demonstrate biochemical and potentially clinical progression of their disease. Neoadjuvant systemic therapy before radical prostatectomy (RP) is a logical strategy to improve treatment outcomes for men with clinically localized high-risk prostate cancer. Furthermore, delivery of chemotherapy and other systemic agents before RP affords an opportunity to explore the efficacy of these agents with pathologic end points. Neoadjuvant chemotherapy, primarily with docetaxel (with or without androgen deprivation therapy), has demonstrated feasibility and safety in men undergoing RP, but no study to date has established the efficacy of neoadjuvant chemotherapy or neoadjuvant chemohormonal therapies. Other novel agents, such as those targeting the vascular endothelial growth factor receptor, epidermal growth factor receptor, platelet-derived growth factor receptor, clusterin, and immunomodulatory therapeutics, are currently under investigation. r 2014 Elsevier Inc. All rights reserved.

Keywords: High-risk prostate cancer; Neoadjuvant therapy; Chemotherapy; Novel therapeutics

Introduction Prostate cancer is the most common cancer and the second leading cause of cancer mortality in men in the United States, with an estimated 233,000 new cases expected in 2014 [1]. Although there are many definitions of high-risk clinically localized prostate cancer, the National Comprehensive Cancer Network definition includes men with any of the following characteristics: prostate-specific antigen (PSA) level 420 ng/ml, clinical stage ZT3, or Gleason grade Z8 [2]. In this cohort, radical prostatectomy (RP) or definitive radiation therapy alone may provide benefit, but many patients develop disease recurrence and progression [3]. Despite advances in surgical techniques, delivery of radiation therapy, and development of novel systemic agents, outcomes of high-risk patients undergoing RP have not improved significantly over time [4].

Corresponding author. Tel.: þ1-646-422-4390; fax: þ1-212-988-0826. E-mail address: [email protected] (J.A. Eastham). *

http://dx.doi.org/10.1016/j.urolonc.2014.11.020 1078-1439/r 2014 Elsevier Inc. All rights reserved.

As a result, multimodality approaches to high-risk prostate cancer have been investigated. Although trials combining radiation therapy with neoadjuvant, concurrent, and adjuvant androgen deprivation therapy (ADT) have demonstrated survival advantages over radiation alone [5], similar benefits have not yet been demonstrated for combining neoadjuvant ADT with RP [6–8]. Neoadjuvant therapy in high-risk clinically localized prostate cancer Treatment of patients with high-risk clinically localized prostate cancer ideally includes strategies directed toward local control of the primary tumor and eradication of microscopic metastatic disease. Toward these goals, multimodality treatment strategies have been used and investigated. The primary goal of both neoadjuvant and adjuvant therapies is to prolong survival of patients with high-risk disease. As compared with adjuvant therapy, neoadjuvant therapy offers the potential benefits of treating patients before any debilitating effects of local treatment and

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E.K. Cha, J.A. Eastham / Urologic Oncology: Seminars and Original Investigations ] (2014) 1–9

downstaging localized or locally advanced tumors, which may potentially facilitate complete resection. Furthermore, studies of neoadjuvant therapy allow for ex vivo determinations of response to systemic treatment through in vivo examination of systemic treatment response (e.g., PSA), ex vivo histopathologic evaluation of RP specimens, or examination of correlative molecular biomarkers. Pathologic end points, such as pathologic complete response (pCR), allow for the treatment of a small number of patients with a relatively short follow-up to establish a signal of efficacy of a neoadjuvant regimen. In other malignancies, such as breast and bladder cancers, pCR following neoadjuvant chemotherapy is a significant predictor of improved clinical outcomes such as disease-free survival and overall survival [9,10]. Whether similar surrogate pathologic end points for neoadjuvant prostate cancer therapies translate into clinical benefit remains to be demonstrated. The neoadjuvant therapy paradigm also allows an opportunity to assess tumor response through surrogate biomarkers in tissue, blood, and other biologic specimen types. Furthermore, there exists the potential to identify prognostic and predictive genetic and molecular markers of response to treatment. Potential drawbacks of evaluating systemic therapies in the neoadjuvant setting include potential delay to surgery, increased rate of complications secondary to effects of treatment, and possible overtreatment of a subset of patients who would not otherwise experience disease recurrence. Neoadjuvant systemic therapy is widely accepted and used in the treatment of patients with localized or locally advanced high-risk solid tumor malignancies, such as breast, bladder, rectal, and esophageal cancers [10–14]. The potential benefit of neoadjuvant therapy combined with the availability of novel agents for prostate cancer has led to the evaluation of multiple regimens including hormonal and chemotherapies in this setting.

Neoadjuvant chemotherapy with or without ADT The rationale for the use of neoadjuvant chemotherapy in patients with high-risk clinically localized prostate cancer arises from randomized clinical trials demonstrating the improved clinical outcomes of men with metastatic castration-resistant prostate cancer (CRPC) treated with chemotherapy [15–17]. A variety of agents have been tested in phase I/II studies of neoadjuvant therapy prior to RP in patients with high-risk or locally advanced prostate cancer (Tables 1–2). These trials have significant variability in terms of defining high-risk prostate cancer/eligibility criteria, chemotherapeutic regimens, duration of treatment, inferred quality of RP, definitions of pathologic end points, use of adjuvant therapies, duration of follow-up, survival end points, and the primary end point selected for analysis.

The duration of treatment in trials evaluating neoadjuvant chemotherapy in patients with high-risk clinically localized prostate cancer has ranged from 6 weeks to 6 months (Table 1) [18–23]. Dreicer et al. [18] performed a phase II study of weekly docetaxel for 6 weeks before RP (n ¼ 29), with a primary end point of surgical feasibility. Secondary end points included change in serum PSA levels, histologic effects, and time to biochemical progression. There was a statistically significant reduction in prechemotherapy vs. postchemotherapy PSA (P o 0.03), but there was residual carcinoma in all cases (pCR ¼ 0%). The authors published a follow-up study with immunohistochemical analysis comparing expression levels of various biomarkers in the pretreatment biopsy and posttreatment RP specimens [19]. They speculated that the absence of meaningful differences in expression levels of various cell cycle and apoptotic biomarkers could explain the lack of clinically significant response to neoadjuvant docetaxel. Febbo et al. [20] published a phase II study that included 19 patients treated with 6 months of docetaxel before RP. The primary study end point was pCR; no patients achieved pCR. However, there was evidence of antitumor activity, as 11 patients (58%) had PSA level reduction of more than 50% and magnetic resonance imaging (MRI) measurements of tumor volume demonstrated maximum reduction of at least 25% in 13 patients (68%) and at least 50% in 4 patients (21%). Similarly, a phase II trial of 2 cycles of neoadjuvant nab-paclitaxel weekly for 3 weeks during a 4week cycle (n ¼ 19) identified no pathologic complete responders [22]. Although these studies of neoadjuvant chemotherapy alone demonstrated feasibility and some signals of biologic efficacy, the absence of pCR and lack of evidence of improved clinical outcomes have dampened enthusiasm for this approach. Other studies have evaluated neoadjuvant chemotherapy in combination with ADT (Table 2) [24–33]. The first trial to demonstrate a pCR in high-risk prostate cancer with neoadjuvant chemohormonal therapy was reported by Prayer-Galetti et al. [28]. In their phase II study of 22 patients with high-risk prostate cancer as defined by ZcT3 disease, Gleason score Z 8, or PSA level Z15 ng/ml, they identified 1 patient (5%) with a pCR, and 6 (32%) with “substantial” pathologic response, which was defined as involving r10% of the RP specimen. In these 6 patients, the residual tumor was confined to small foci and was comprised of single cells or small groups of glands, with prominent cytoplasmic vacuolization. At a median follow-up of 53 (range: 30–64) months, 8 patients (42%) remained free of biochemical recurrence. The Canadian Uro-Oncology Group conducted the largest phase II trial of neoadjuvant chemohormonal therapy and reported on 72 men with high-risk prostate cancer [29]. These patients were treated with docetaxel (weekly for 6 weeks in an 8-week cycle for 3 cycles) and ADT (buserelin acetate every 8 weeks for 3 doses and nilutamide for the first 4 weeks) followed by RP. Of the 64 patients completing

Neoadjuvant chemotherapy Trial

Patients (n) Selection criteria

Regimen

Duration

Outcomes pCR, % PSM, % PFS, %

OS

Follow-up, median (range)

Dreicer et al. (2004) [18] Magi-Galluzzi et. al (2007) [19] Febbo et al. (2005) [20]

29

cT2b-cT3, Gleason score Z 8, or PSA level 415 ng/ml

Docetaxel (weekly  6 weeks)

6 Weeks

0

4

71 43

NR NR

23 (1.5–36) 49 (23–72)

19

Docetaxel (weekly  6 months)

6 Months

0

NR

44

NR

26 (4.5–40)

Friedman et al. (2008) [21]

15

cT3, or Gleason score Z 8, or PSA level Z20 ng/ml, or Gleason score 4 þ 3 with SVI on MRI and 45 positive cores 4cT2, or Gleason score Z 8, or PSA level Z 15 ng/ml

0

55

38

NR

17 (9–34)

Shepard et al. (2009) [22]

19

0

NR

NR

NR

NR

Garzotto et al. (2010) [23]

57

0

33

Layton et al. (2012) [46]

16

0

50

66% At 2 NR years and 50% at 5 years NR NR

Docetaxel (weekly for 3 weeks in 3–6 Months 4-week cycle) and capecitabine (every 2 weeks in 4-week cycle  3–6 cycles) 2 Months cT2b-cT3, or Gleason score Z 8, or PSA Nab-paclitaxel (weekly for 3 weeks in 4-week cycle  2 level Z15 ng/ml, or any Gleason score 5 components, or Gleason score 4 þ 3 cycles) in Z3 cores, or Z30% chance of BCF within 5 years cT2c-cT3a, or Gleason score Z 4 þ 3, or Docetaxel and escalating 4 Months any Gleason score 5 components, or mitoxantrone (weekly for 3 PSA level Z15 ng/ml weeks in 4-week cycle  4 cycles) cT3, or Gleason score Z 8, or PSA Ixabepilone (weekly  12–16 3–4 Months level Z20 ng/ml, or cT2 Gleason score weeks) 4þ3

BCF ¼ biochemical failure; NR ¼ not reported; OS ¼ overall survival; PFS ¼ progression-free survival; PSM ¼ positive surgical margins, SVI ¼ seminal vesicle invasion.

63 (7–88)

NR

E.K. Cha, J.A. Eastham / Urologic Oncology: Seminars and Original Investigations ] (2014) 1–9

Table 1 Trials of neoadjuvant chemotherapy without androgen deprivation therapy before radical prostatectomy

3

4

Trial

Patients (n)

Selection criteria

Regimen

Duration

Outcomes pCR, %

Pettaway et al. (2000) [24]

33

Clark et al. (2001) [25] Hussain et al. (2003) [47] Konety et al. (2004) [26] Silberstein et al. (2014) [27] Prayer-Galetti et al. (2007) [28]

18 21 36

cT3, or cT1-2 and Gleason score Z 8, or cT2b-cT2c, and Gleason score 7 and PSA level Z10 ng/ml cT2b-cT3, or Gleason score Z 8, or PSA level Z15 ng/ml ZcT2b, or Gleason score Z 8, or PSA level Z15 ng/ml ZcT3, or Gleason score Z 8, or PSA level 420 ng/ml

34 22

ZcT3, or Gleason score Z 8, or PSA level Z15 ng/ml

Chi et al. (2008) [29] 72

ZcT3, or Gleason score Z 8, or PSA level Z20 ng/ml

Sella et al. (2008) [30]

22

ZcT2c, or Gleason score Z 8, or PSA level Z20 ng/ml

Mellado et al. (2009) 57 [31]

cT3, or Gleason score Z 7 (4 þ 3), or PSA level Z20 ng/ml

Womble et al. (2011) 22 [32] Narita et al. (2012) 18 [33]

cT3, or Gleason score Z 8 or Z4 þ 3, or PSA level 420 ng/ml cT3, or Gleason score 4 9, or PSA level Z15 ng/ml

PSM, %

PFS, %

0

17

69

NR

13 (9–18)

Etoposide þ estramustine (daily for 3 3 Months weeks in 4-week cycle  3 cycles) Docetaxel þ estramustine (in 3-week 9–18 Weeks cycle  3–6 cycles) LHRH agonist þ estramustine þ 4–6 Months paclitaxel þ carboplatin (weekly in 4-week cycle)  4–6 cycles

0

13

88

NR

14 (5–20)

0

30

71

NR

13 (NR)

0

22

45

NR

29 (5–51)

0

24

27

NR

LHRH agonist þ docetaxel þ estramustine (3-week cycle  4 cycles) LHRH agonist þ AA þ docetaxel (weekly for 6 weeks in 8-week cycle  3 cycles) LHRH agonist þ AA þ docetaxel þ estramustine (3-week cycle  4 cycles) LHRH agonist þ AA þ docetaxel (weekly for 3 weeks in 4-week cycle  3 cycles) Ketoconazole þ docetaxel (3-week cycle  4 cycles) LHRH agonist þ AA þ docetaxel þ estramustine (weekly  6 weeks)

3 Months

5

26

42

NR

53 (30–64)

6 Months

3

27

70

NR

42 (25–66)

3 Months

0

27

54

100

23 (12.1–54.7)

3 Months

6

35

65

NR

35 (23–47)

3 Months

0

42

36.4

NR

18 (3–40)

6 Weeks

11

0

77

NR

18 (1–49)

KAVE þ LHRH agonist þ AA  3 months

3 Months

OS, %

Follow-up, median (range)

134 (NR)

AA ¼ antiandrogen; KAVE ¼ ketoconazole, doxorubicin, vinblastine, and estramustine; LHRH ¼ luteinizing hormone–releasing hormone; NR ¼ not reported; OS ¼ overall survival; PFS ¼ progressionfree survival; PSM ¼ positive surgical margins.

E.K. Cha, J.A. Eastham / Urologic Oncology: Seminars and Original Investigations ] (2014) 1–9

Table 2 Trials of neoadjuvant chemotherapy with androgen deprivation therapy before radical prostatectomy

6 Vuky et al. [48]

Vuky et al. [38] 30 Febbo et al. [39] 11 Mathew et al. [40] 36

AA ¼ antiandrogen; LHRH ¼ luteinizing hormone–releasing hormone; NR ¼ not reported; OS ¼ overall survival; PFS ¼ progression-free survival; PSM ¼ positive surgical margins; VEGF ¼ vascular endothelial growth factor.

NR NR NR 3 Months 0

NR

28 (10–42) NR 39 (NR) NR NR 94 67 NR 53 33 NR 18 2 Months 0 6 Weeks 0 18 Weeks 0

Gefitinib þ docetaxel EGFR Imatinib PDGFR Imatinib þ docetaxel þ LHRH PDGFR agonist þ AA Docetaxel þ GVAX Immune

NR NR 51 32

pCR rate, % PSM, % PFS, % OS, %

18 Weeks 0 VEGF Bevacizumab þ docetaxel

cT3a-cT3b, or Gleason score Z 8, or Gleason score 7 and cT3 by MRI, or PSA level Z20 ng/ml, or PSA velocity Z2 ng/ml/y cT2b-cT3, or Gleason score Z 8, or PSA level Z20 ng/ml NR ZcT2c, or Gleason score Z 8, or PSA level 420 ng/ml, or cT2b Gleason score 7 with PSA level 410 ng/ml NR 41 Ross et al. [36]

Patients (n) Selection criteria Trial

Table 3 Published trials of neoadjuvant targeted agents before radical prostatectomy

Regimen

Target

Duration

Outcomes

Follow-up, median (range)

E.K. Cha, J.A. Eastham / Urologic Oncology: Seminars and Original Investigations ] (2014) 1–9

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protocol therapy, 2 (3%) had a pCR and 16 (25%) had minimal residual disease, defined as an estimated tumor volume of r5% in the RP specimen. There were 43 patients (53%) with pT2 disease, 17 (27%) with positive surgical margins, and 4 (6%) with lymph node–positive disease. The authors reported that 19 patients (30%) had biochemical recurrence with a median follow-up of 42.7 months. Konety et al. [26] reported on 36 patients treated with neoadjuvant chemohormonal therapy consisting of estramustine, paclitaxel, carboplatin, and goserelin acetate. Enrollment criteria included high-risk prostate cancer, defined by having any of the following criteria: clinical stage ZcT3, Gleason score Z 8, or PSA level 420 ng/ml. Patients were treated with 4 to 6 cycles of chemohormonal therapy. The positive surgical margin rate was 22%, and no patients experienced a pCR. At a median follow-up of 29 months, 45% of patients remained free from biochemical recurrence. We recently published a long-term update of the oncologic outcomes from this trial, with a median follow-up of 13.1 years [27]. The 10-year progression-free, diseasespecific, and overall survival probabilities were 22%, 84%, and 78%, respectively. These trials provide evidence that neoadjuvant chemotherapy with or without ADT results in decreased disease burden as assessed by a variety of biochemical, radiologic, and pathologic parameters. Whether these results will translate into a clinically significant benefit in the phase III setting remains to be determined. To that end, the Cancer and Leukemia Group B is currently conducting a multicenter phase III randomized trial of neoadjuvant chemohormonal therapy [34,35]. The Cancer and Leukemia Group B 90203 trial is designed with a target accrual of 750 patients who will be randomized to either neoadjuvant chemohormonal therapy with docetaxel (six 21-day cycles) and a luteinizing hormone–releasing hormone agonist followed by RP with staging pelvic lymphadenectomy or surgery alone. Eligible patients must have 1 criterion for high-risk disease, which is defined as a nomogram-predicted probability of r60% freedom from biochemical recurrence at 5 years or Gleason score Z 8 disease. The primary end point is 3-year biochemical progression-free survival.

Neoadjuvant novel therapies As discussed, the paradigm of neoadjuvant therapy before RP provides an opportunity to investigate novel agents for early signals of biologic activity through the pathologic and molecular evaluation of RP specimens. Potential targets under investigation in the neoadjuvant setting include angiogenesis, the epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), clusterin, and immunotherapeutic approaches. The results from several trials investigating novel therapeutics have been reported (Table 3) and others are ongoing (Table 4).

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A multicenter phase II trial evaluated the efficacy of neoadjuvant docetaxel with bevacizumab, a humanized monoclonal antibody that binds to and neutralizes serum vascular endothelial growth factor, which is a mediator of tumor angiogenesis [36]. In total, 41 patients with high-risk prostate cancer, defined by having one or more of the following characteristics: T3 disease (clinical or by MRI), Gleason score Z 8, PSA level Z20 ng/ml, or PSA velocity Z 2 ng/ml/y, were treated with docetaxel (every 21 d for 6 cycles) and bevacizumab (for cycles 1–5). The primary end point was partial response as evaluated by endorectal coil MRI. In total, 12 patients (29%) achieved a 450% reduction in tumor volume and 9 patients (22%) achieved a 50% posttreatment decline in PSA level. There were no complete pathologic responses; 32% of patients had positive surgical margins. Sunitinib, a multitargeted receptor tyrosine kinase inhibitor with activity against the vascular endothelial growth factor receptor, was studied in a phase II trial of 44 patients treated with neoadjuvant sunitinib with leuprolide for 3 months followed by RP [37]. Eligibility criteria included high-risk disease, defined as ZcT3 disease with Gleason score Z 8 and PSA level Z20 ng/ml, or cT2b–cT2c disease with Gleason score 7 and PSA level Z10 ng/ml. In total, 35 patients completed treatment and 2 (6%) achieved the primary end point of pCR. At a median follow-up of 35 months, 15 patients (43%) remained free of disease. Gefitinib, a small-molecule tyrosine kinase inhibitor of EGFR that has demonstrated antiproliferative activity against prostate cancer cell lines, was studied in a phase II trial of 30 patients [38]. Patients with high-risk disease, defined as cT2b–cT3 disease, or Gleason score Z 8, or PSA level Z20 ng/ml, were treated with neoadjuvant docetaxel and gefitinib for 2 months before RP. No patients met the primary end point of pCR. At a median follow-up of 28 months, 20 patients (67%) were biochemically free of disease with no additional therapy. Given that the data regarding EGFR inhibition in prostate cancer in both neoadjuvant and metastatic trials have been disappointing, enthusiasm for this approach has waned. The inhibition of PDGFR has also been studied in the neoadjuvant setting. Imatinib, a tyrosine kinase inhibitor with activity against PDGFR was studied in neoadjuvant trials either alone or in combination with docetaxel and ADT [39,40]. In one study, 36 men with high-risk prostate cancer, defined as ZcT3 disease, Gleason score Z 8 with cT2c disease or PSA level 420 ng/ml, or Gleason score Z 7 with cT2b disease and PSA level 410 ng/ml, were treated with docetaxel weekly for 4 weeks in a 6-week cycle, imatinib, and leuprolide for 3 cycles (18 wk) before RP [40]. There were no pCRs; 18% of patients had positive surgical margins. At a median follow-up of 39 months, 53% of patients remained free from biochemical progression. As with EGFR, the results with PDGFR inhibition in both the neoadjuvant and the metastatic settings have not been promising.

Clusterin, a stress-activated cytoprotective chaperone that confers treatment resistance in many malignancies, including CRPC, has also been studied as a neoadjuvant target for high-risk prostate cancer. OGX-011, an oligonucleotide antisense inhibitor targeting clusterin, was studied in combination with ADT in a phase I study of 25 men with high-risk prostate cancer [41]. OGX-011 was well tolerated and resulted in dose-dependent decreases of clusterin expression in prostate tissue and lymph nodes. As a result, future trials may be conducted to investigate the clinical efficacy of this agent [42]. The results with sipuleucel-T, an active cellular immunotherapy consisting of autologous peripheral blood mononuclear cells that have been activated ex vivo with a recombinant fusion protein, in metastatic CRPC have led to renewed interest in immunotherapeutics for prostate cancer [43]. Investigators of a study examining neoadjuvant sipuleucel-T recently presented their results regarding recruitment of effector T cells into the tumor rim [44]. Other neoadjuvant trials with immunomodulatory agents, including ipilimumab, granulocyte-macrophage colonystimulating factor, GVAX, and rituximab, are ongoing (Table 4).

Conclusions Neoadjuvant therapy before RP has not yet been established as a standard of care given the absence of demonstrated clinical benefit in phase III clinical trials. There have been some encouraging results for certain neoadjuvant therapies with improvements in intermediate end points such as reductions in tumor volume, reductions in positive surgical margin rates, and PSA response. However, given the low rate of pCR in these trials, development of novel therapeutics and combination therapies is likely needed. Nevertheless, neoadjuvant trials before RP provide an important opportunity to test the preliminary efficacy of novel agents and to advance our understanding of prostate cancer. As neoadjuvant trials afford the ability to test tumor tissue before and after treatment, studies may be able to elucidate mechanisms of treatment resistance. Identification of prognostic and predictive biomarkers may allow for more effective selection of cohorts for targeted therapeutics. However, investigators need to be aware of the potential undefined long-term risks of chemotherapy and novel therapeutics and must carefully select both agents and patient cohorts [45]. The ultimate goal of neoadjuvant therapies in patients with high-risk prostate cancer is that early use of new and more potent hormonal, immune, and chemotherapies will lead to improved survival outcomes. In the near future, we anticipate that there will be studies investigating optimal perioperative regimens for different therapeutics and the completion of phase III trials aimed at definitively

Table 4 Ongoing clinical trials evaluating novel targeted agents in the neoadjuvant setting PI

Institution/sponsor/ collaborator

Target

Neoadjuvant treatment

Estimated enrollment

Outcome measures

NCT00526591

Garcia

Case Comprehensive Cancer Center National Cancer Institute

mTOR

Everolimus

17

11 - pCR, surgical margins, and extracapsular extension

University of California, San Francisco Novartis

PI3K

24

11 - Safety and tolerability 21 - PSA doubling time and immunohistochemical staining of biomarkers 11 - PI3K inhibition in prostate tumor tissue (phospho-S6)

University of British Columbia Department of Defense

Clusterin

45

21 21 21 11

-

PI3K inhibition in prostate tumor tissue (phospho-4EBP1) PI3K inhibition in prostate tumor tissue (phospho-AKT) PSA response pCR

38

21 21 21 21 11

-

Intraprostatic clusterin expression, OGX-011 levels Safety and tolerability Clusterin expression in peripheral blood mononuclear cells Time to PSA nadir and progression-free survival pCR

NCT01695473

NCT00138918

NCT00589472

Febbo

Chi

Slovin

BKM120

OGX-011þADT

Memorial Sloan Kettering HDAC Cancer Center National Cancer Institute

VorinostatþLHRH agonistþAA

NCT01832259

Agarwal

University of Utah

VEGFR

Pazopanib

30

NCT01409200

Zurita

VEGFR

AxitinibþADT

54

NCT01385059

Pal

MD Anderson Cancer Center Pfizer City of Hope Medical Center National Cancer Institute

21 - PSA level, testosterone, DHT, DHEA, DHEA-S in blood from RP specimens; testosterone, androstenedione, androstenediol, DHT, DHEA, and DHEA-S in prostate tissue 21 - Gene and protein expression analysis of AR target genes, PSA, TMPRSS2 21 - Safety and tolerability 11 - Decrease in premetastatic niche formation in LNs 21 - Progression-free survival 21 - Safety and tolerability 11 - Progression-free survival

VEGFR

Axitinib

60

11 - Decrease in premetastatic niche (VEGFR1 clusters) in LNs

MD Anderson Cancer Center Pfizer Beth Israel Deaconess Medical Center Duke University Genentech, Sanofi University of California, San Francisco Dendreon

VEGFR

SunitinibþADT

64

21 21 21 11

VEGF

Bevacizumabþdocetaxel

42

11 - Radiographic response by endorectal MRI

NCT00329043

Zurita et al. [37]

NCT00321646

Taplin

NCT00715104

Fong

-

Safety and tolerability Progression-free survival Metastasis-free survival pCR

E.K. Cha, J.A. Eastham / Urologic Oncology: Seminars and Original Investigations ] (2014) 1–9

Identifier

21 - PSA response Immune

Sipuleucel-T

40

11 - Immune response within prostate tissue 21 - Immunologic and immunohistochemical biomarkers 7

Dreicer

Klein Antonarakis

Howell

NCT00400517

NCT01696877

NCT01804712

21 - PSA response, peripheral B cells, and serum CXCL13

DHT ¼ dihydrotestosterone; GM-CSF ¼ granulocyte-macrophage colony-stimulating factor; HDAC ¼ histone deacetylase; LNs ¼ lymph nodes; PI: principal investigator; VEGF ¼ vascular endothelial growth factor; VEGFR ¼ vascular endothelial growth factor receptor.

Sharma NCT01194271

University of California, San Diego Genentech

Immune

Rituximab

18

11 - Intraprostatic CD8þT cell infiltration 11 - Safety and tolerability 21 - Intraprostatic CD4þ T cell and Treg infiltration, tissue androgen concentrations, pCR, PSA response, progression-free survival 11 - Histologic response rate 32 GVAXþADTþ cyclophosphamide Immune

11 - pCR, surgical margins, PSA response, and progression-free survival 29 GM-CSFþthalidomide Immune

20 IpilimumabþADT Immune

11 - Safety and tolerability 24 GM-CSF Immune Fong NCT00305669

University of California, San Francisco National Cancer Institute MD Anderson Cancer Center Bristol-Myers Squibb Case Comprehensive Cancer Center National Cancer Institute Sidney Kimmel Comprehensive Cancer Center

Outcome measures Estimated enrollment Neoadjuvant treatment Target Institution/sponsor/ collaborator PI Identifier

Table 4 Continued

11 - Immunological variables measured on peripheral blood and tumor tissue samples

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establishing efficacy. We also expect that additional novel therapeutic agents that are currently being studied in patients with metastatic disease may similarly merit consideration for testing in the neoadjuvant setting.

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