Curr Oncol Rep (2015) 17:44 DOI 10.1007/s11912-015-0468-7

GENITOURINARY CANCERS (DP PETRYLAK AND JW KIM, SECTION EDITORS)

Chemotherapy in Prostate Cancer Michael Hurwitz 1

# Springer Science+Business Media New York 2015

Abstract For approximately a decade, chemotherapy has been shown to prolong life in patients with metastatic castration-resistant prostate cancer (mCRPC). Since that time, however, only two agents have proven to prolong life (docetaxel and cabazitaxel). However, in the last year, the addition of chemotherapy to primary hormonal therapy became a standard of care for high-volume castration-sensitive metastatic disease. Here I will review current prostate cancer chemotherapies, mechanisms of resistance to those therapies, and ongoing clinical studies of chemotherapy combinations and novel chemotherapeutics. Keywords mCRPC . CSPC . Taxanes . Docetaxel . Cabazitaxel . Mitoxantrone . Taxotere . Jevtana . Novantrone . Chemohormonal . Prostate . Neuroendocrine . Small cell . Adenocarcinoma . Microtubules . PSA

Introduction Unlike most solid tumors, chemotherapy is not the major treatment for advanced prostate cancer. Therapies aimed at decreasing androgen signaling are the mainstay of therapy and have been so for most of a century. Recently, new drugs to target different aspects of androgen signaling have been brought into clinical practice, resulting in impressive responses in metastatic prostate cancer. However, these This article is part of the Topical Collection on Genitourinary Cancers * Michael Hurwitz [email protected] 1

Yale Comprehensive Cancer Center, 333 Cedar Street, New Haven, CT 06520, USA

therapies invariably fail to control disease, and chemotherapy is central to treating both advanced adenocarcinoma of the prostate as well as neuroendocrine variants. Furthermore, in the last year, the indications for chemotherapy use were broadened by evidence of benefit in earlier disease. Here I will review the currently approved chemotherapies in prostate cancer as well as other agents that might be used in the future.

Historical Perspectives Most treatment-naïve metastatic prostate cancer will respond to androgen deprivation. However, almost all patients will eventually progress to metastatic castration-resistant prostate cancer (mCRPC). Therefore, in the 1970s and 1980s, numerous chemotherapeutics were tested in CRPC. These studies suffered from methodological difficulties because prostate cancer metastasizes primarily to the bone, and changes in bony disease are often not measurable radiographically. Prostate-specific antigen (PSA) testing was not used until the 1990s. Thus, many studies used disease stabilization as an endpoint despite the lack of evidence that it correlated with meaningful outcomes. Most agents were tested in the phase II setting, and although there were many that seemed promising, eventually none were shown to prolong survival. In an influential review on the subject from 1985, Eisenberger et al. showed the survival curves of a large number of these drug trials superimposed on each other in a single graph [1]. This graph became known as the Bspaghetti curve,^ and it showed that most of the curves were quite similar. Nonetheless, one chemotherapeutic, estramustine, was approved from studies done in this era. Estramustine is comprised of two moieties, an alkylating agent and an estrogenic compound. Upon uptake into cells, the two parts of the compound split. The rationale behind the use of estramustine in

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prostate cancer was that the estrogen would oppose androgen signaling and the alkylater would act like traditional chemotherapy by alkylating DNA. However, functional studies have demonstrated that estramustine has neither of those activities. Rather, estramustine binds to and depolymerizes microtubules. Furthermore, the affects on microtubules account for its antineoplastic activity [2]. Multiple trials were done in the pre-PSA era, none of which showed almost any objective responses for estramustine as a single agent but based on a perception of clinical benefit it was approved in 1984 [1]. The anthracenedione mitoxantrone (Novantrone) was the first chemotherapeutic to be approved for metastatic prostate cancer in the PSA era. A study by the National Cancer Institute of Canada compared treatment with mitoxantrone and prednisone to prednisone alone [3]. Addition of mitoxantrone to prednisone increased the palliative response, which was the primary endpoint, from 12 to 29 %. A subsequent study, CALGB9182, compared mitoxantrone and hydrocortisone to hydrocortisone alone [4]. There was no difference in overall survival (12.3 vs 12.6 months), the primary endpoint, but the mitoxantrone-containing arm had a longer time to treatment failure and disease progression. In addition, there were nonsignificant trends towards improvement in quality of life with mitoxantrone. Based on its palliative benefit, mitoxantrone was approved for use in metastatic prostate cancer by the FDA. While mitoxantrone is no longer used very commonly because of the effectiveness of taxanes (see below), it is a well-tolerated drug that can palliate symptoms. Furthermore, because of its quality of life improvement but lack of survival benefit, it became the control arm for subsequent studies on more active agents.

Taxanes Mechanisms of Action The breakthrough in cytotoxic chemotherapy for prostate cancer came with the taxanes. Taxanes (e.g., paclitaxel (Taxol), docetaxel (Taxotere), cabazitaxel (Jevtana)), derived from the Pacific Yew tree, stabilize microtubules (MTs). MTs are hollow tubes formed from stacks of αand β-tubulin heterodimers that are key structural elements in all cells. MTs are normally quite dynamic, forming and breaking down cyclically; binding of taxanes to β-tubulin disrupts this process. The enforced change in microtubule dynamics by taxanes activates a number of cellular pathways that results in cell crisis and apoptosis [5]: 1. Mitotic block: inhibition of MT dynamics causes dysfunction of the mitotic spindle, blocking progression through mitosis and eventually activating the apoptotic cascade [6]. Notably, this occurs at concentrations 100fold lower than those required to induce MT stabilization,

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arguing that stabilization per se is less important than alteration of MT dynamics. 2. Activation of Bcl-2: MT stabilization activates the proapoptotic protein Bcl-2 by phosphorylation [7, 8]. Bcl-2 activation is mediated by the serine/threonine kinase cRaf, a component of the Ras-MAPK pathway, as demonstrated by the lack of Bcl-2 phosphorylation in cells lacking c-Raf [8]. However, in vitro, docetaxel is 100 times more potent than paclitaxel for induction of phosphorylation of Bcl-2, while activity of the two agents is not that different in vivo, arguing against either the importance or the in vivo validity of this mechanism. 3. Androgen receptor signaling: several reports have shown that treatment of cancer cells with taxanes decreases the translocation of the androgen receptor (AR) to the nucleus, which is required for its primary function of transcriptional activation of target genes. The AR binds to MTs directly and perhaps, stabilization of MTs sequesters the AR in the cytoplasm. In one study, the level of AR nuclear localization in a paclitaxel-treated prostate cancer cell line (LNCaP) was under 20 % of that in control-treated cells [9]. In the same study, though, only slightly fewer prostate cancer samples treated with paclitaxel had nuclear AR than untreated samples (38 vs 50 %). This difference was still statistically significant, but the biological significance is unclear. In another study, also in LNCaP cells, 70 % of untreated cells had nuclear AR compared to 35 % in paclitaxel-treated cells [10]. However, de Leeuw et al. [11•] found that exposure of LNCaP cells to docetaxel or cabazitaxel had no effect on the nuclear localization of the AR. Thus, more study will be needed to show how much this mechanism contributes to prostate cancer treatment in vivo. 4. AR-independent transcription: one study assessed both AR and other activities in 22Rv1 cells, a CRPC cell line [12]. They found that paclitaxel treatment decreased AR transcription, consistent with an effect on the AR described above but also that AR-independent genes were altered. For example, expression of maspin and FOXO1, both of which oppose AR function were increased. In addition, the tumor suppressor PTEN was required for the affect on AR transcription, which has been implicated in prostate cancer pathogenesis [13].

Docetaxel in mCRPC Two phase III studies published in 2004 showed that docetaxel prolonged overall survival (OS) in CRPC. The TAX 327 study randomized 1006 men with mCRPC to docetaxel given weekly, docetaxel given every 3 weeks or to mitoxantrone [14]. Patients on all study arms received daily prednisone as well. Patients receiving docetaxel on the 3-week schedule had improved OS compared to those on the mitoxantrone arm (18.9 vs 16.5 months, p=0.009; PSA

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RR 48 %). Pain, quality of life, and PSA responses were also significantly improved. For this review, a PSA response is defined as ≥50 % decrease in the PSA unless otherwise specified. Patients on the weekly docetaxel arm also had improved survival over the mitoxantrone arm, but the improvement did not reach statistical significance. The Southwestern Oncology Group’s SWOG 99-16 trial randomized 770 men with mCRPC to two arms. One received docetaxel and estramustine and the other received mitoxantrone and prednisone, both given every 3 weeks [15]. Like the TAX 327 study, OS, time to progression, and PSA responses were significantly improved in the patients who received docetaxel (OS 17.5 vs 15.6 months, p=0.02; PSA RR 50 %). Although the regimens from both the TAX 327 and SWOG 99-16 trials were approved, the prednisone-containing regimen has become the standard because of ease of use. In addition, a later study that randomized patients to docetaxel/prednisone with or without estramustine found that the estramustine-containing arm actually had a non-significantly shorter OS (19.3 vs 21 months) [16]. The combination of docetaxel and prednisone given every 3 weeks has remained unchanged for the last 11 years though a 2-week schedule (50 mg/m2) was compared to the 3-week schedule (75 mg/m2) in a multicenter phase III trial. The 2week schedule had a significantly longer time to treatment failure and a better toxicity profile. However, the study has not been repeated and so has not become used widely [17]. Notably, the value of prednisone in this regimen has been called into question by more recent studies of docetaxel in castration-sensitive prostate cancer (CSPC) where docetaxel alone provides significant benefits (see below). Cabazitaxel in mCRPC Taxanes, including docetaxel, have a high affinity for P-glycoprotein (also called the multidrug resistance protein (MDR)), one of the several proteins responsible for efflux of chemotherapeutics from cells. The secondgeneration taxane cabazitaxel was developed to have much less P-glycoprotein binding [18]. In the phase III TROPIC trial, 755 men with mCRPC that had progressed after treatment with docetaxel were randomized to cabazitaxel or mitoxantrone [19]. Patients on both arms received prednisone. OS, progression-free survival (PFS), and PSA response were significantly better in patients treated with cabazitaxel (OS 15.1 vs 12.7 months, HR for death 0.7, p<0.0001). In addition to differences in P-glycoprotein binding, one recent study has shown that cabazitaxel and docetaxel have somewhat different effects on cancer cells [11•]. Chemohormonal Therapy in Castration-Sensitive Prostate Cancer Given the OS advantage for docetaxel in CRPC, it was studied earlier in the disease course. Specifically, three trials were designed to assess the potential benefit of adding

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docetaxel chemotherapy to androgen deprivation therapy (ADT) for patients who present with metastatic disease: 1. ECOG3805, the CHAARTED trial, randomized 790 men to receive either ADT alone or ADT and six cycles of docetaxel chemotherapy (without concomitant prednisone). Primary endpoint was overall survival (OS). Patients were stratified based on the extent of disease into low- vs high-volume disease (>4 bony metastases, any metastases outside of the vertebral column or pelvis, extranodal visceral metastases) since disease outcome has been shown to be associated with these parameters [20, 21]. With a median follow-up of 29 months, OS was significantly improved with docetaxel (57.6 vs 44.0 months, p=0.0003). The OS difference for highvolume disease was even more dramatic (49.2 vs 32.2 months, p=0.0006) whereas no difference was detected for low-volume disease, but these data are not yet mature (median OS was not reached for either arm of the study in the low-volume group). Time to progression, time to the development of CRPC, and percentages of patients with PSA <0.2 ng/mL at 6 and 12 months were all statistically significantly improved in the docetaxelcontaining arm [22••]. 2. The French GETUG-AFU 15 trial attempted to answer the same question [23•]. Three hundred eighty-five men were randomized to receive ADT alone or in combination with up to nine cycles of docetaxel. Three-year OS was 64.2 vs 62.9 %. However, biochemical PFS and clinical PFS were both significantly longer in the ADT+docetaxel group (22.9 vs 12.9 months, p = 0.005, and 23.5 vs 15.4 months, p=0.015, respectively). Updated results from this study were presented at the 2015 ASCO genitourinary symposium [24•]. At a median follow-up of 82.9 months, the median OS was 46.5 vs 60.9 months in the ADT vs ADT+docetaxel arms. Despite this large difference, it was not statistically significant. Subgroup analysis of high- and low-volume disease did not show a difference in OS between those groups either. It is unclear why these two studies have such differing results, though the GETUG subgroup analyses are on much smaller populations and are retrospective. Furthermore, a smaller percentage of patients were in the high disease burden group than in the CHAARTED study, further weakening its power to detect an OS difference. It is striking that despite the dramatically different results by statistical analysis, the actual median OS differences for the whole populations from ECOG3805 and GETUG-AFU 15 are quite similar (13 vs 14.4 months). 3. The STAMPEDE trial (Systemic Therapy in Advanced or Metastatic Prostate Cancer: Evaluation of Drug Efficacy, NCT00268476) by the Medical Research Council in Great Britain is analyzing a number of different therapies

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in combination with ADT in mCSPC (www.stampedetrial.org). Part of the trial randomized 1087 men with mCSPC (M1) to ADT alone or with six cycles of docetaxel but did not stratify patients according to disease volume. OS was the primary endpoint. Addition of docetaxel resulted in an OS hazard ratio of 0.73 (0.59, 0.89), which was highly significant (p=0.002). Failure-free survival (FFS) was also improved with docetaxel (HR 0.62 (0.54, 0.73)). STAMPEDE also enrolled patients with M0 disease (elevated PSA but no evidence of disease on imaging). In these patients, OS was not improved by the addition of docetaxel (HR 1.01 (0.65, 1.56)) but FFS was (HR 0.57 (0.42, 0.76)) [25••]. Chemohormonal therapy has also been investigated in the neoadjuvant setting. A number of phase II studies have assessed the value of combining docetaxel with androgen deprivation prior to prostatectomy. Overall, the rate of pathological complete responses is quite low (range 0–10 % of published studies) [26]. CALGB90203 (NCT00430183) is a randomized phase III trial comparing docetaxel+ADT to no therapy prior to prostatectomy in high-risk localized disease, which should answer this question. This trial is still accruing patients. Current Use of Chemotherapy in Prostate Cancer Based on the data from the CHAARTED and STAMPEDE trials, patients with high-volume castration-sensitive prostate cancer (CSPC) are treated with ADT and six cycles of docetaxel chemotherapy. Some are using this regimen in all newly metastatic disease, but the data in this setting are not as clear since STAMPEDE did not stratify by disease volume, and the lowvolume disease data from CHAARTED are not yet mature. For mCRPC, docetaxel chemotherapy is used until progression. At that point, there are a number of choices for treatment depending on what else the patient has received prior to docetaxel. Options include abiraterone acetate, enzalutamide, radium-223, Sipuleucel-T (Provenge), and second-line chemotherapy with cabazitaxel [27]. Aside from cabazitaxel, all of these medications are approved for treatment prior to docetaxel as well as after it but sequencing of agents in mCRPC is beyond the scope of this review. Patients who progress on cabazitaxel or those who cannot tolerate cabazitaxel can receive mitoxantrone for palliation of symptoms. See Table 1 for study details. Resistance Mechanisms Several mechanisms of resistance to taxanes have been demonstrated in cell lines, and others proposed: 1. Multidrug resistance: a number of proteins of the ATPbinding cassette (ABC) transporter family are expressed in cancer cells and promote efflux of chemotherapeutics

2.

3.

4.

5.

from those cells [28]. Taxanes are targets of these proteins. Expression of ABCB1 (also called MDR1 and Pglycoprotein 1), ABCC4, and ABCB5 have all been shown to cause resistance to taxanes in cell lines though cabazitaxel is far less sensitive to this mechanism than other taxanes. For example, its activity is <10-fold as sensitive as docetaxel is to ABCB1 expression and is almost completely insensitive to ABCC4 expression (it was not tested in ABCB5) [29, 30•, 31, 32]. Epithelial-mesenchymal transition (EMT): several studies have found that EMT decreases sensitivity to taxanes, including cabazitaxel [30•, 33]. Although the mechanisms have not been fully worked out, roles for microRNAs and the EMT inducer ZEB1 have been demonstrated in cell lines [33, 34]. AR splice variant expression: advanced prostate cancers often express splice variants of the AR. The best studied is the AR-V7 splice variant, which lacks the ligand binding domain and is constitutively active. AR-V7 expression confers resistance to taxanes, while a second mutant AR-V567 does not. AR-V7 does not bind to MTs whereas AR-V567 does. Possibly AR-V7 avoids sequestration in the cytoplasm by MT binding, allowing it to function in the presence of taxanes. These data support the idea that taxanes function at least partially through downregulation of AR signaling (see above) [35•, 36]. Furthermore, Antonarakis et al. [37] recently reported in abstract form that the response rate to docetaxel in patients with any AR-V7 transcript in circulating tumor cells was lower than in those lacking the variant (41 vs 65 %, p=0.19), though the difference did not reach statistical significance in the small population studied (n=37). A number of other AR changes have been proposed to cause taxane resistance (AR overexpression, increased androgen biosynthesis, AR coactivator expression, and activation of alternative AR signaling pathways), but none of these have been demonstrated experimentally. Tubulin alterations: overexpression of the β-tubulin III isoform confers taxane resistance (including cabazitaxel), most likely because there is decreased taxane binding to that isoform [30•, 38]. Martello et al. [39] describe a mutation in α-tubulin that results in changes to microtubule-associated protein (MAP) binding, resulting in changes in MT dynamics, which also causes taxane resistance. A third potential mechanism is overexpression of the ERG protein, a key prostate cancer protein. ERG directly binds MTs and inhibits taxane binding [40]. Poor tissue penetration: Kyle et al. [41] found poor tissue penetration of taxanes in xenografts and in threedimensional in vitro models. Thus, tissue concentrations might not be high enough in vivo to cause effective cell killing.

ECOG 3805

mCSPC

d

c

b

a

ADT

Comparator

Eligibility for trials

20.7 vs 14.7 Not reported Not reported 22.9 vs 12.9 15.2 vs 9.2 40.9 vs 22.4 FFS HR 0.62 FFS HR 0.57 FFS HR 0.62 Not reported 6.3 vs 3.2 8.8 vs 5.4 Not reported 3.7 vs 2.3

17.5 vs 15.6 15.1 vs 12.7 No difference 12.3 vs 12.6

[26]

[14]

Not reported

45 vs 32

18.7 vs 14.3

Not reported

[4]

[3]

[15] [19]

[23, 24]

Not reported

50 vs 27 39.2 vs 17.8

[22]

Not reported

bPFS (months)a PSA response (%)b Ref

57.6 vs 14.7 49.2 vs 32.2 Not reached 60.9 vs 46.5 39 vs 35.1 83.1 vs not reached HR 0.76 HR 1.01 HR 0.73 18.9 vs 16.5

OS (months)a

These trials were performed prior to the approval of docetaxel in prostate cancer. Currently the use of these agents is in the post-docetaxel setting (please see text)

Trial subsets

>50 % decrease in PSA

Compared to comparator arm

Docetaxel/ADT

Agent

ECOG PS <2 High volumec Low volumec GETUG-AFU 15 Docetaxel/ADT ADT KPS ≥70 High volumec Low volumec STAMPEDE Docetaxel/ADT ADT WHO PS ≤2 M0c M1c mCRPC TAX 327 Docetaxel/prednisone Mitoxantrone/prednisone ECOG PS ≤2, no CNS spread, neuropathy < grade 2 SWOG 99-16 Docetaxel/estramustine Mitoxantrone/prednisone ECOG PS ≤2 mCRPC: TROPIC Cabazitaxel/prednisone Mitoxantrone/prednisone ECOG PS ≤2, neuropathy post-docetaxel ≤ grade 2 NCIC unnamedd Mitoxantrone/prednisone Prednisone ECOG PS ≤3, ≥3 month life expectancy Mitoxantrone/hydrocortisone Hydrocortisone ECOG PS ≤2 CALGB 9182d

Trial

Phase III studies of currently approved chemotherapies in metastatic prostate cancer

Indication

Table 1

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At this time, strategies to combat resistance are not well established. In the case of MDR, cabazitaxel is less sensitive and perhaps, we should consider moving it into the first-line setting for mCRPC instead of docetaxel. For the AR splice variants, small molecules are being developed that bind to them (as opposed to the currently available hormonal agents, none of which target AR-V7 [42]). For the other mechanisms of resistance described, new treatments or, in the case of poor tissue penetration, possibly new delivery systems will need to be developed. Combination Therapies A large number of trials combining taxanes with drugs that have different mechanisms of action have been tried to increase activity without increasing toxicity. To date, no combinations have proved beneficial over taxanes alone though some are still in testing. Among the agents that have already been shown not to benefit are bone-targeting agents (atrasentan [43], dasatinib [44], zibotentan [45]), antiangiogenesis agents (bevacizumab [46], aflibercept [47], lenalidomide [48], vitamin D (calcitriol [49])) and the proapoptotic agent oblimersen [50]. Possibly, since none of these drugs has significant clinical activity as a single agent, the use of more effective drugs in combination will have better results [51–53]. The bone-targeting radiopharmaceutical Radium223 (Xofigo) has been tested in combination with docetaxel in a phase I/II study, which showed that bone alkaline phosphatase normalized in 91 % (21/23) of patients on the combination vs 55 % with docetaxel alone (6/11) [54]. Although not statistically significant, the results are provocative. Two antisense compounds are also currently in trials. The anti-clusterin antisense compound custirsen has been combined with both docetaxel in a randomized trial (NCT00258388) and with cabazitaxel in a non-randomized trial (NCT01578655). The results of these studies are pending. Several trials combining highly active hormonal agents with taxanes are underway. Docetaxel has been combined with the Cyp17A inhibitor orteronel [55] and the antiandrogen enzalutamide [56]. Mateo et al. [57] reported in abstract form that the combination of cabazitaxel and abiraterone after docetaxel and abiraterone separately had a 46 % PSA response rate and a 20 % partial response rate. Though this is in a small number of patients, these results appear promising. The ABICABAZI trial (NCT02218606) is randomizing patients to abiraterone vs abiraterone and cabazitaxel currently. Combination chemotherapies, too, have been tried. A small randomized phase II trial comparing docetaxel/prednisone to docetaxel/prednisone/cyclophosphamide showed no difference in response rate [58]. Regan et al. [59] analyzed seven phase I and II studies that combined carboplatin with either docetaxel or paclitaxel. Response rates were high (69–73 %), but overall survival did not appear significantly different from single-agent docetaxel. However, platinum/taxane

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combinations have a role in neuroendocrine-differentiated prostate cancers (see below). Lastly, the results of a phase I study of cabazitaxel and mitoxantrone in chemotherapy-naïve patients were presented recently and demonstrated a 44 % PSA response rate [60]. It is unclear if this is an improvement over single agents.

Non-Taxane Chemotherapeutics Aside from mitoxantrone, which was discussed above, cyclophosphamide and carboplatin are occasionally used in mCRPC. These therapies have demonstrated responses but no proven overall survival benefit. Several small nonrandomized studies have assessed low-dose oral cyclophosphamide in this setting [61–64]. The largest of these studies found a PSA response rate of 34.5 % in 80 patients given 50 mg/m2 of oral cyclophosphamide daily with a mediation response duration of 7.5 months. Carboplatin at 150 mg/m2 weekly was evaluated in 27 patients with minimal effects (26.9 % of patients had a PSA that declined, but none of the response were >50 % decline) [65]. A study in the early 1990s in 25 patients demonstrated a 17 % partial response rate in evaluable patients and a 20 % PSA response rate [66]. Although these results are not terribly compelling, both cyclophosphamide and low-dose carboplatin are very welltolerated and, therefore, are acceptable choices for a patient who has progressed on all current therapies but is ineligible for clinical trials and has a reasonable performance status. Novel agents assessed include platinums, epothilones, and eribulin. Satraplatin did not demonstrate an overall survival benefit [67]. Ixabepilone, an epothilone anti-tubulin agent, was analyzed in 42 patients. 14/42 pts (33 %) had PSA responses and the median PFS and OS were 6 and 18 mo, respectively [68]. Liu et al. (2012) [69] showed a 20-35 % RR (depending on whether patients were chemotherapy-naïve or not). Currently a randomized trial (NCT00058084) is comparing ixabepilone to mitoxantrone/prednisone. Harzstark et al. [70] assessed the combination of mitoxantrone and ixabepilone in 56 patients with at least three cycles of prior taxane therapy and found that 25/56 (45 %) had PSA responses and 8/36 (22 %) had PRs. PFS was 4.4 months, and OS was 12.5 months. Another microtubule inhibitor, Eribulin mesylate, was tested in 108 patients, 50 of whom had previous taxane therapy. The PSA RR in taxane-naïve patients was 24 % but only 8.5 % in taxane pre-treated patients [71]. Lastly, a chemotherapeutic monomethyl auristatin E conjugated to an antibody aimed at the prostate antigen PSMA (PSMA-ADC) has been tested in a phase II trial in patients who have progressed on taxanes. Thirty six percent of patients had a PSA decline of ≥30 %, and 80 % had stable disease. Despite its targeting to prostate tissue, there was significant systemic toxicity including fatigue and neutropenia [72]. Nonetheless,

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the principle of better targeting of chemotherapeutics to tumors to improve the therapeutic window of these agents, especially in heavily pretreated patients, can be tried in the future.

Neuroendocrine/Small Cell Prostate Cancer Though the majority of prostate cancers are adenocarcinomas driven by androgen receptor signaling, there is a small subset, estimated at approximately 5 % of advanced disease, that have neuroendocrine or small cell histology and either produce very little or no PSA. One study characterized the features of this disease: low PSA, lytic bony metastases, visceral disease, bulky disease, short response to ADT, histology, elevated circulating neuroendocrine markers, or hypercalcemia [73••]. These cancers are not responsive to hormonal treatments and do not respond to single-agent taxanes. Traditionally, they have been treated with small cell cancer regimens, such as etoposide/platinum combinations, but most of these responses are transient. Flechon et al. [74] treated 60 patients with neuroendocrine prostate cancer with carboplatin/etoposide and demonstrated a 8.9 % ORR in the 46 patients with measurable disease. Median OS in this group was only 9.6 months. Papandreou et al. [75] showed a 61 % PR with etoposide/cisplatin/doxorubicin, but toxicity was severe, and OS was 10.5 months. An alternative regimen, docetaxel/cisplatin, was studied by Culine et al. [76]. In 41 patients with prostate cancers with neuroendocrine differentiation, they found a 33 % RR in the 29 patients with measurable disease, 45 % clinical benefit (e.g., pain improvement), and an OS of 12 months. Aparicio et al. [73••] combined two regimens by treating 113 patients with carboplatin/docetaxel until progression and then treating with etoposide/cisplatin. Median OS was 16 months. While the neuroendocrine/small cell subtype of prostate cancer is a small subgroup, this might not always be the case. These cancers develop within adenocarcinomas. As our treatments directed at the androgen receptor improve, it is possible that androgen independence associated with metaplasia to neuroendocrine cancer might develop in increasing frequency. Thus, the difficulty treating this type of disease might become a much more significant problem in the future.

Conclusions Despite the lower profile of chemotherapy in prostate cancer agents, if anything, the role of chemotherapy is increasing. Furthermore, as better anti-hormonal agents are used, the biology of the disease is likely to change so that a larger proportion of truly androgen-independent cancers are seen, which

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will probably increase the use of current chemotherapies as well as other novel agents. Compliance with Ethics Guidelines

Conflict of Interest Michael Hurwitz declares that he has no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.

2.

3.

4.

5. 6.

7. 8.

9.

10.

11.•

Eisenberger MA, Simon R, O'Dwyer PJ, Wittes RE, Friedman MA. A reevaluation of nonhormonal cytotoxic chemotherapy in the treatment of prostatic carcinoma. J Clin Oncol. 1985;3:827–41. Dahllöf B, Billström A, Cabral F, Hartley-Asp B. Estramustine depolymerizes microtubules by binding to tubulin. Cancer Res. 1993;53:4573–81. Tannock IF, Osoba D, Stockler MR, Ernst DS, Neville AJ, Moore MJ, et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol. 1996;14:1756–64. Kantoff PW, Halabi S, Conaway M, Picus J, Kirshner J, Hars V, et al. Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the cancer and leukemia group B 9182 study. J Clin Oncol. 1999;17:2506–13. Jordan MA, Wilson L. Microtubules as a target for anticancer drugs. Nat Rev Cancer. 2004;4:253–65. Jordan MA, Wendell K, Gardiner S, Derry WB, Copp H, Wilson L. Mitotic block induced in HeLa cells by low concentrations of paclitaxel (taxol) results in abnormal mitotic exit and apoptotic cell death. Cancer Res. 1996;56:816–25. Haldar S, Basu A, Croce CM. Bcl2 is the guardian of microtubule integrity. Cancer Res. 1997;57:229–33. Blagosklonny MV, Schulte T, Nguyen P, Trepel J, Neckers LM. Taxol-induced apoptosis and phosphorylation of Bcl-2 protein involves c-Raf-1 and represents a novel c-Raf-1 signal transduction pathway. Cancer Res. 1996;56:1851–4. Zhu M-L, Horbinski CM, Garzotto M, Qian DZ, Beer TM, Kyprianou N. Tubulin-targeting chemotherapy impairs androgen receptor activity in prostate cancer. Cancer Res. 2010;70:7992– 8002. Darshan MS, Loftus MS, Thadani-Mulero M, Levy BP, Escuin D, Zhou XK, et al. Taxane-induced blockade to nuclear accumulation of the androgen receptor predicts clinical responses in metastatic prostate cancer. Cancer Res American Association for Cancer Research; 2011;71:6019–29. de Leeuw R, Berman-Booty LD, Schiewer MJ, Ciment SJ, Den RB, Dicker AP, et al. Novel actions of next-generation taxanes benefit advanced stages of prostate cancer. Clin Cancer Res. 2015;21:795– 807. This paper describes differences between the activities of

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cabazitaxel and docetaxel and suggests mechanisms by which cabazitaxel has anti-tumor efficacy when docetaxel does not. 12. Gan L, Chen S, Wang Y, Watahiki A, Bohrer L, Sun Z, et al. Inhibition of the androgen receptor as a novel mechanism of taxol chemotherapy in prostate cancer. Cancer Res American Association for Cancer Research; 2009;69:8386–94. 13. Carver BS, Chapinski C, Wongvipat J, Hieronymus H, Chen Y, Chandarlapaty S, et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell. 2011;19:575–86. 14. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502–12. 15. Petrylak DP, Tangen CM, Hussain MHA, Lara PN, Jones JA, Taplin ME, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351:1513–20. 16. Machiels J-P, Mazzeo F, Clausse M, Filleul B, Marcelis L, Honhon B, et al. Prospective randomized study comparing docetaxel, estramustine, and prednisone with docetaxel and prednisone in metastatic hormone-refractory prostate cancer. Am J Clin Oncol. 2008;26:5261–8. 17. Kellokumpu-Lehtinen P-L, Harmenberg U, Joensuu T, McDermott R, Hervonen P, Ginman C, et al. 2-weekly versus 3-weekly docetaxel to treat castration-resistant advanced prostate cancer: a randomised, phase 3 trial. Lancet Oncol. 2013;14:117–24. 18. Mita AC, Denis LJ, Rowinsky EK, Debono JS, Goetz AD, Ochoa L, et al. Phase I and pharmacokinetic study of XRP6258 (RPR 116258A), a novel taxane, administered as a 1-hour infusion every 3 weeks in patients with advanced solid tumors. Clin Cancer Res. 2009;15:723–30. 19. de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels J-P, Kocak I, 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: 1147–54. 20. Eisenberger MA, Blumenstein BA, Crawford ED, Miller G, McLeod DG, Loehrer PJ, et al. Bilateral orchiectomy with or without Flutamide for metastatic prostate cancer. N Engl J Med. 1998;339:1036–42. 21. Millikan RE, Wen S, Pagliaro LC, Brown MA, Moomey B, Do KA, et al. Phase III trial of androgen ablation with or without three cycles of systemic chemotherapy for advanced prostate cancer. Am J Clin Oncol. 2008;26:5936–42. 22.•• Sweeney C, Chen Y-H, Carducci M, Liu G, Jarrard F, Eisenberger M et al. Impact on overall survival (OS) with chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic prostate cancer (mPrCa): An ECOG-led phase III randomized trial. J Clin Oncol. 2014;pp. supp–abstrLBA2. This abstract presents the data from the CHAARTED trial that provides the rationale for chemohormonal therapy in high volume newly metastatic prostate cancer. 23.• Gravis G, Fizazi K, Oudard S, Priou F, Esterni B, Latorzeff I, et al. Androgen-deprivation therapy alone or with docetaxel in noncastrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol. 2015;14: 149–58. This paper and the following abstract [24] present data from the GETUG-AFU 15 study that contradict the results of the CHAARTED and STAMPEDE studies [22]. These data call into question the use of chemohormonal therapy for high volume newly metastatic prostate cancer. 24.• Gravis G, Boher J-M, Joly F, Oudard S, Albiges L, Priou F et al. Androgen deprivation therapy (ADT) plus docetaxel (D) versus ADT alone for hormone-naïve metastatic prostate cancer (PCa): long-term analysis of the GETUG-AFU 15 phase III trial. J Clin Oncol. 2015;pp. suppl7–abstr140.

Curr Oncol Rep (2015) 17:44 25.•• James ND, Sydes MR, Mason MD, Clarke NW, Dearnaley DP, Spears RM et al. Docetaxel and/or zoledronic acid for hormonenaïve prostate cancer: first overall survival results from STAMPEDE (NCT00268476 J Clin Oncol. 2015;pp. suppl– abstr5001. This abstract presents the data from the S TA M P E D E t ri a l th a t p ro v i de s th e r a t i o n a l e fo r chemohormonal therapy in newly metastatic prostate cancer. 26. Cha EK, Eastham JA. Chemotherapy and novel therapeutics before radical prostatectomy for high-risk clinically localized prostate cancer. Urol Oncol. 2015. 27. Hurwitz M, Petrylak DP. Sequencing of agents for castrationresistant prostate cancer. Oncology. 2013;27:1144–9–54–8 (Williston Park, N.Y). 28. Kawai K, Sakurai M, Sakai T, Misaki M, Kusano I, Shiraishi T, et al. Demonstration of MDR1 P-glycoprotein isoform expression in benign and malignant human prostate cells by isoform-specific monoclonal antibodies. Cancer Lett. 2000;150:147–53. 29. Oprea-Lager DE, Bijnsdorp IV, van Moorselaar RJA, van den Eertwegh AJM, Hoekstra OS, Geldof AA. ABCC4 decreases docetaxel and not cabazitaxel efficacy in prostate cancer cells in vitro. Anticancer Res. 2013;33:387–91. 30.• Duran GE, Wang YC, Francisco EB, Rose JC, Martinez FJ, Coller J, et al. Mechanisms of resistance to cabazitaxel. Mol Cancer Ther. 2015;14:193–201. This paper demonstrates a number of mechanisms of resistance to cabazitaxel chemotherapy. Understanding these mechanisms will be central to the development of therapies to circumvent resistance. 31. Sánchez C, Mercado A, Contreras HR, Mendoza P, Cabezas J, Acevedo C, et al. Chemotherapy sensitivity recovery of prostate cancer cells by functional inhibition and knock down of multidrug resistance proteins. Prostate. 2011;71:1810–7. Wiley Subscription Services, Inc. A Wiley Company. 32. Kawanobe T, Kogure S, Nakamura S, Sato M, Katayama K, Mitsuhashi J, et al. Expression of human ABCB5 confers resistance to taxanes and anthracyclines. Biochem Biophys Res Commun. 2012;418:736–41. 33. Puhr M, Hoefer J, Schäfer G, Erb HHH, Oh SJ, Klocker H, et al. Epithelial-to-mesenchymal transition leads to docetaxel resistance in prostate cancer and is mediated by reduced expression of miR200c and miR-205. Am J Pathol. 2012;181:2188–201. 34. Marín-Aguilera M, Codony-Servat J, Reig Ò, Lozano JJ, Fernández PL, Pereira MV, et al. Epithelial-to-mesenchymal transition mediates docetaxel resistance and high risk of relapse in prostate cancer. Mol Cancer Ther. 2014;13:1270–84. 35.• Thadani-Mulero M, Portella L, Sun S, Sung M, Matov A, Vessella RL, et al. Androgen receptor splice variants determine taxane sensitivity in prostate cancer. Cancer Res. 2014;74:2270–82. This paper describes the mechanism of action in prostate cancer cell lines by which one androgen receptor splice variant confers taxane resistance while another one remains taxane sensitive. Delineating these mechanisms of action are necessary to develop treatments to evade resistance. 36. Martin SK, Bañuelos CA, Sadar MD, Kyprianou N. N-terminal targeting of androgen receptor variant enhances response of castration resistant prostate cancer to taxane chemotherapy. Mol Oncol. 2014;9:628–39. 37.• Antonarakis ES, Lu C, Chen Y, Luber B, Wang H, Nakazawa M et al. AR splice variant 7 (AR-V7) and response to taxanes in men with metastatic castration- resistant prostate cancer (mCRPC). J Clin Oncol. 2015;pp. 1–2. In a recent paper, Antonarakis et al. (ref 41) showed that the presence of the AR-V7 splice variant caused 100 % resistance to enzalutamide and abiraterone. In this follow up study, they show that in some AR-V7 harboring cancers taxanes still work. 38. Ploussard G, Terry S, Maillé P, Allory Y, Sirab N, Kheuang L, et al. Class III beta-tubulin expression predicts prostate tumor

Curr Oncol Rep (2015) 17:44

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52. 53. 54.

aggressiveness and patient response to docetaxel-based chemotherapy. Cancer Res American Association for Cancer Research; 2010;70:9253–64. Martello LA, Verdier-Pinard P, Shen H-J, He L, Torres K, Orr GA, et al. Elevated levels of microtubule destabilizing factors in a taxolresistant/dependent A549 cell line with an alpha-tubulin mutation. Cancer Res. 2003;63:1207–13. Galletti G, Matov A, Beltran H, Fontugne J, Miguel Mosquera J, Cheung C, et al. ERG induces taxane resistance in castrationresistant prostate cancer. Nat Commun. 2014;5:5548. Kyle AH, Huxham LA, Yeoman DM, Minchinton AI. Limited tissue penetration of taxanes: a mechanism for resistance in solid tumors. Clin Cancer Res. 2007;13:2804–10. Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer protocol. N Engl J Med. 2014;371:1028–38. Quinn DI, Tangen CM, Hussain M, Lara PN, Goldkorn A, Moinpour CM, et al. Docetaxel and atrasentan versus docetaxel and placebo for men with advanced castration-resistant prostate cancer (SWOG S0421): a randomised phase 3 trial. Lancet Oncol. 2013;14:893–900. Araujo JC, Trudel GC, Saad F, Armstrong AJ, Yu E, Bellmunt J et al. Overall survival (OS) and safety of dasatinib/docetaxel versus docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC): Results from the randomized phase III READY trial. J Clin Oncol. 2013;pp. 1–2. Fizazi KS, Higano CS, Nelson JB, Gleave M, Miller K, Morris T, et al. Phase III, randomized, placebo-controlled study of docetaxel in combination with zibotentan in patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2013;31:1740–7. Kelly WK, Halabi S, Carducci M, George D, Mahoney JF, Stadler WM, et al. Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without Bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401. J Clin Oncol. 2012;30:1534–40. Tannock IF, Fizazi K, Ivanov S, Karlsson CT, Fléchon A, Skoneczna I, et al. Aflibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer (VENICE): a phase 3, doubleblind randomised trial. Lancet Oncol. 2013;14:760–8. Petrylak DP, Vogelzang NJ, Budnik N, Wiechno PJ, Sternberg CN, Doner K et al. Docetaxel and prednisone with or without lenalidomide in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (MAINSAIL): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2015. Scher HI, Jia X, Chi K, de Wit R, Berry WR, Albers P, et al. Randomized, open-label phase III trial of docetaxel plus highdose calcitriol versus docetaxel plus prednisone for patients with castration-resistant prostate cancer. J Clin Oncol. 2011;29:2191–8. Tolcher AW, Chi K, Kuhn J, Gleave M, Patnaik A, Takimoto C, et al. A phase II, pharmacokinetic, and biological correlative study of oblimersen sodium and docetaxel in patients with hormonerefractory prostate cancer. Clin Cancer Res. 2005;11:3854–61. Nelson JB, Love W, Chin JL, Saad F, Schulman CC, Sleep DJ, et al. Phase 3, randomized, controlled trial of atrasentan in patients with nonmetastatic, hormone-refractory prostate cancer. Cancer. 2008;113:2478–87. Nabhan C, Petrylak DP. The role of IMiDs alone or in combination in prostate cancer. Clin Genitourin Cancer. 2012;10:141–6. Miller K, Moul JW, Gleave M, Fizazi K, Nelson JB, Morris T, et al. pcan20132a. Prostate Cancer Prostatic Dis. 2013;16:187–92. Morris MJ, Higano CS, Scher HI, Sweeney C, Antonarakis ES, Shevrin D et al. Effects of radium-223 dichloride (Ra-223) with docetaxel (D) versus D on prostate-specific antigen (PSA) and bone alkaline phosphatase (bALP) in patients (pts) with castration-

Page 9 of 10 44

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

resistant prostate cancer (CRPC) and bone metastases (mets): a phase 1/2a clinical trial. J Clin Oncol. 2015;pp. 1–2. Petrylak DP, Gandhi JG, Clark WR, Heath E, Lin J, Oh WK, et al. Phase 1/2 study of orteronel (TAK-700), an investigational 17,20lyase inhibitor, with docetaxel-prednisone in metastatic castrationresistant prostate cancer. Invest New drugs. US: Springer; 2015. p. 1–12. Fleming M, Rathkopf D, Gibbons J, Peterson A, Hannah A, Forer D et al. Enzalutamide in combination with docetaxel in men with prostate cancer (PC): preliminary results from a phase I study. J Clin Oncol. 2013;pp. 1–1. Mateo J, Fizazi K, Pezaro C, Loriot Y, Mehra N, Albiges L et al. Phase 1/2 trial of cabazitaxel with abiraterone acetate in patients with metastatic castration- resistant prostate cancer (mCRPC) progressing after docetaxel and abiraterone acetate: phase 2 results. J Clin Oncol. 2015;pp. 1–2. Porsch M, Ulrich M, Wendler JJ, Liehr U-B, Reiher F, Janitzky A, et al. A randomised phase II trial comparing docetaxel plus prednisone with docetaxel plus prednisone plus low-dose cyclophosphamide in castration-resistant prostate cancer. Chemotherapy. 2015;60:129–34. Regan MM, O'Donnell EK, Kelly WK, Halabi S, Berry W, Urakami S, et al. Efficacy of carboplatin-taxane combinations in the management of castration-resistant prostate cancer: a pooled analysis of seven prospective clinical trials. Ann Oncol. 2010;21: 312–8. Oxford University Press. Aggarwal R, Bryce A, Weinberg VK, Ryan CJ, Derleth CL, Harzstark AL et al. A multicenter phase I study of cabazitaxel (Cbz), mitoxantrone (Mito), and prednisone (Pred) (CAMP) for chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2015;pp. 1–2. Lord R, Nair S, Schache A, Spicer J, Somaihah N, Khoo V, et al. Low dose metronomic oral cyclophosphamide for hormone resistant prostate cancer: a phase II study. J Urol. 2007;177:2136–40. discussion2140. Maulard-Durdux C, Dufour B, Hennequin C, Chrétien Y, Delanian S, Housset M. Phase II study of the oral cyclophosphamide and oral etoposide combination in hormone-refractory prostate carcinoma patients. Cancer. 1996;77:1144–8. Glode LM, Barqawi A, Crighton F, Crawford ED, Kerbel R. Metronomic therapy with cyclophosphamide and dexamethasone for prostate carcinoma. Cancer. 2003;98:1643–8. Wiley Subscription Services, Inc. A Wiley Company. Raghavan D, Cox K, Pearson BS, Coorey GJ, Rogers J, Watt WH, et al. Oral cyclophosphamide for the management of hormonerefractory prostate cancer. Br J Urol. 1993;72:625–8. Matos CS, de Carvalho ALMB, Lopes RP, Marques MPM. New strategies against prostate cancer–Pt(II)-based chemotherapy. Curr Med Chem. 2012;19:4678–87. Canobbio L, Guarneri D, Miglietta L, Decensi A, Oneto F, Boccardo F. Carboplatin in advanced hormone refractory prostatic cancer patients. Eur J Cancer. 1993;29A:2094–6. Sternberg CN, Petrylak DP, Sartor O, Witjes JA, Demkow T, Ferrero J-M, et al. Multinational, double-blind, phase III study of prednisone and either satraplatin or placebo in patients with castrate-refractory prostate cancer progressing after prior chemotherapy: the SPARC trial. Am J Clin Oncol. 2009;27:5431–8. Hussain M, Tangen CM, Lara PN, Vaishampayan UN, Petrylak DP, Colevas AD, et al. Ixabepilone (epothilone B analogue BMS247550) is active in chemotherapy-naive patients with hormonerefractory prostate cancer: a Southwest Oncology Group trial S0111. J Clin Oncol. 2005;23:8724–9. Liu G, Chen Y-H, Dipaola R, Carducci M, Wilding G. Phase II trial of weekly ixabepilone in men with metastatic castrate-resistant prostate cancer (E3803): a trial of the Eastern Cooperative Oncology Group. Clin Genitourin Cancer. 2012;10:99–105.

44 70.

Page 10 of 10

Harzstark AL, Rosenberg JE, Weinberg VK, Sharib J, Ryan CJ, Smith DC, et al. Ixabepilone, mitoxantrone, and prednisone for metastatic castration-resistant prostate cancer after docetaxelbased therapy: a phase 2 study of the Department Of Defense Prostate Cancer Clinical Trials Consortium. Cancer. 2011;117: 2419–25. Wiley Subscription Services, Inc. A Wiley Company. 71. de Bono JS, Molife LR, Sonpavde G, Maroto JP, Calvo E, Cartwright TH, et al. Phase II study of eribulin mesylate (E7389) in patients with metastatic castration-resistant prostate cancer stratified by prior taxane therapy. Ann Oncol. 2012;23:1241–9. Oxford University Press. 72. Petrylak DP, Smith DC, Appleman LJ, Fleming M, Hussain A, Dreicer R et al. A phase 2 trial of prostate-specific membrane antigen antibody drug conjugate (PSMA ADC) in taxane-refractory metastatic castration- resistant prostate cancer (mCRPC). J Clin Oncol. 2014;pp. 1–2. 73.•• Aparicio AM, Harzstark AL, Corn PG, Wen S, Araujo JC, Tu S-M, et al. Platinum-based chemotherapy for variant castrate-resistant prostate cancer. Clin Cancer Res. 2013;19:3621–30. This paper describes chemotherapy regimens for neuroendocrine prostate

Curr Oncol Rep (2015) 17:44 cancers and more importantly, defines features of neuroendocrine/small cell prostate cancer. In addition to helping clinicians know which cancers should be treated this way, defining these features will help to define the appropriate population for future neuroendocrine cancer treatment studies. 74. Flechon A, Pouessel D, Ferlay C, Perol D, Beuzeboc P, Gravis G, et al. Phase II study of carboplatin and etoposide in patients with anaplastic progressive metastatic castration-resistant prostate cancer (mCRPC) with or without neuroendocrine differentiation: results of the French Genito-Urinary Tumor Group (GETUG) P01 trial. Ann Oncol. 2011;22:2476–81. Oxford University Press. 75. Papandreou CN, Daliani DD, Thall PF, Tu S-M, Wang X, Reyes A, et al. Results of a phase II study with doxorubicin, etoposide, and cisplatin in patients with fully characterized small-cell carcinoma of the prostate. J Clin Oncol. 2002;20:3072–80. 76. Culine S, El Demery M, Lamy P-J, Iborra F, Avancès C, Pinguet F. Docetaxel and cisplatin in patients with metastatic androgen independent prostate cancer and circulating neuroendocrine markers. J Urol. 2007;178:844–8.