Neoadjuvant Androgen Deprivation Therapy in Prostate Cancer

Updated: Oct 21, 2022
  • Author: Rutveej Patel, MD, MS; Chief Editor: Edward David Kim, MD, FACS  more...
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Neoadjuvant androgen deprivation therapy (NADT) is systemic therapy administered after the diagnosis of prostate cancer but before locoregional therapy such as radical prostatectomy (RP) or radiation. With NADT prior to RP, the intent is to eradicate malignant androgen-dependent cells, in the hope that sufficient tumor regression will permit complete resection of residual prostate cancer, improving pathologic outcome and survival. The role of preoperative androgen deprivation remains controversial, however.

The use of NADT arose in response to the limitations of RP. RP is most likely to cure patients with organ-confined disease. However, owing to the inaccuracy of clinical staging, approximately 50% of men with clinical stage T1 or T2 prostate cancer have tumor extension outside of the prostate capsule, and 5-40% have positive surgical margins. Approximately 20-30% of men with 1 or more positive margins experience relapse, depending on the site of the positive margin, preoperative prostate-specific antigen (PSA) level, Gleason score, and presence of seminal vesical invasion.

Incomplete surgical resection leaves patients at increased risk for local recurrence and progression. In addition, despite considerable advances in prostate cancer research, high-risk, localized prostate cancer remains an extremely refractory disease. Single-modality treatment offers a 5-year, biochemical, disease-free survival rate of no better than 50%.

Those concerns regarding prostate cancer progression have led to a renewed interest in the use of NADT prior to RP. The advent of safe and reversible forms of androgen deprivation, such as luteinizing hormone–releasing hormone (LHRH) analogues and antiandrogens (AAs), has also contributed to enthusiasm for NADT. 

Most trials have used 3 months of NADT and have demonstrated a significant decrease in prostate volume by 20-50% and in serum PSA levels by more than 90%. A significant increase in organ-confined disease and a decrease in the incidence of positive margins have also been reported.

However, no randomized or nonrandomized study using 3 months of NADT has shown any statistically significant benefit in terms of overall and disease-free survival. Some preliminary results show that increasing the duration of therapy to 6 or 8 months further reduces tumor volume and PSA nadir levels and decreases the likelihood of positive margins. Moreover, it is possible that a subset of patients is likely to benefit from neoadjuvant therapy; this population of patients has yet to be defined, but its parameters may become clearer as the optimal duration and form of NADT is defined.

Treatment and research considerations

Many unanswered questions exist regarding the benefit of NADT. Current data are insufficient to support the routine recommendation of NADT. Until this ambiguity is clarified, the utility of NADT prior to RP will remain controversial.

In patients with clinically localized prostate cancer, the National Comprehensive Cancer Network (NCCN) strongly discourages the use of NADT before RP outside of a clinical trial. However, the NCCN notes that androgen deprivation therapy before, during, and/or after radiation prolongs survival in selected patients who are receiving radiation therapy only. In patients with regional (N1) prostate cancer and a life expectancy > 5 years, the NCCN guidelines support the use of external beam radiation therapy (EBRT) and NADT. [1]

However, a meta-analysis of the sequencing of androgen deprivation therapy with radiation therapy in localized prostate cancer concluded that adjuvant androgen deprivation therapy results in superior outcomes, compared with neoadjuvant or concurrent androgen deprivation therapy. The 15-year progression-free survival was 36% with adjuvant therapy versus 29% with neoadjuvant therapy (P = 0.01). Adjuvant therapy was also superior with respect to biochemical failure, distant metastasis, and metastasis-free survival. Long-term toxicity rates were comparable. [2]

As with any therapy, the ultimate benefit of NADT in prostate cancer will be determined only through properly designed trials with long-term follow-up. Also, hormone therapy is associated with significant side effects, such as hot flushes and gynecomastia, as well as financial costs. [3]

The decision to use hormone therapy should, therefore, be taken at a local level, between the patient, clinician, and policy maker, taking into account the clinical benefits, toxicity, and cost. More research is needed to guide the choice, the duration, and the schedule of hormone deprivation therapy and the impact of long-term hormone therapy with regard to toxicity and the patient’s quality of life.

However, neoadjuvant therapy may provide an important paradigm for the discovery of active agents for the treatment of prostate carcinoma, in addition to improving clinical outcomes for men with early, high-risk disease. The availability of pretherapy and posttherapy tumor specimens enables the determination of biologic and pathologic antitumor activity with a relatively small number of patients. A multidisciplinary approach with a team of oncologists and urologists will be critical to making advances in the arena of neoadjuvant therapy for prostate carcinoma and efficiently evaluating new therapies.

There is a particularly strong need for neoadjuvant chemotherapy trials that will allow more rapid and less costly screening of new drugs and drug regimens. Research to date has identified some possible candidates.

A study of the multikinase inhibitor sunitinib in patients with newly diagnosed prostate cancer prior to prostatectomy concluded that sunitinib appears safe and tolerable, with a toxicity profile similar to that seen in patients with advanced cancer. Changes in proliferation and apoptosis in treated patients suggest a treatment effect. [4]

Sipuleucel-T is an immunotherapy that the US Food and Drug Administration (FDA) has approved for use in asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer. In a phase II trial of 41 patients, Fong et al found that neoadjuvant use of sipuleucel-T induced both a systemic antigen-specific T-cell response and recruited activated effector T-cells into the prostate tumor microenvironment, primarily at the tumor interface. No downgrading of the Gleason score was noted at the time of RP in comparison to the control group. The authors propose that these findings support the investigation of sipuleucel-T and other immunotherapies in future combination trials. [5]

In a study by Hafron et al in men with advanced prostate cancer, median overall survival was 30.4 months in patients treated with sipuleucel-T plus antiandrogen therapy (typically with enzalutamide), compared with 14.3 months in patients treated with antiandrogen monotherapy (typically with abiraterone). Risk of death was 28.3% lower in the the sipuleucel-T plus antiandrogen cohort than in the antiandrogen monotherapy cohort (hazard ratio 0.717; P <  0.01). [6]

Custirsen (OGX-011) is an experimental agent that inhibits expression of clusterin, a cytoprotective chaperone protein that promotes cell survival and confers broad-spectrum resistance in cancer cell lines. The combination of custirsen with chemotherapy is currently being examined in phase III trials. [7]

A phase II study of neoadjuvant chemohormonal therapy (CHT) with docetaxel and complete androgen blockade in patients with locally advanced, high-risk prostate cancer undergoing RP found that the therapy is feasible despite high hematotoxicity, with excellent functional results. [8] However, in a phase III multicenter randomized trialof neoadjuvant CHT with androgen-deprivation therapy plus docetaxel, the primary end point was not met: 3-year biochemical progression–free survival was no different with CHT plus RP than with RP alone. Some improvement in secondary end points was seen with neoadjuvant CHT, but the investigators caution that any potential benefit must be weighed against toxicity. [9]

Unfortunately, use of the platelet-derived growth factor receptor (PDGFR) inhibitor imatinib mesylate has proved ineffective against prostate cancer, in both the neoadjuvant and the adjuvant setting; indeed, PDGFR inhibition may accelerate advanced forms of prostate cancer. [10]


Androgen Deprivation

In 1941, Huggins and Hodges won the Nobel Prize for first demonstrating the effect of androgen withdrawal on benign and malignant prostate tissue. [11] Androgen deprivation induces programmed cell death (apoptosis) and inhibits cell proliferation in malignant prostate tissue. This technique has since become an established part of the management of advanced prostatic carcinoma. 

NADT is also not a new concept; it was introduced more than a half a century ago by Vallet et al. Subsequently, others have studied this concept in more depth. In addition to shrinking tumor, increasing organ confinement, and decreasing the incidence of positive margins, neoadjuvant therapy has also been theorized to treat occult regional and systemic micrometastasis, with the ultimate goal being improved long-term, disease-free survival. [12, 13]

The advent of safe and reversible forms of androgen deprivation such as luteinizing hormone–releasing hormone (LHRH) analogues and antiandrogens (AAs) has spurred a resurgence in enthusiasm for NADT. LHRH agonists exert their effects by initial stimulation of the production of luteinizing hormone (LH) by the pituitary, followed by suppression of LH and testosterone to castration levels within 30 days. AAs counteract the effects of adrenal androgen at the target cell by interfering with binding at the receptor in a competitive manner. Together, these agents provide powerful androgen blockade (see Table 1, below).

Table 1. Agents of Neoadjuvant Androgen Deprivation Therapy (Open Table in a new window)




Adverse Effects



22.5 mg SC q3mo




10.8 mg SC q3mo

LHRH agonists: Initial stimulation of LHRH production (flare) followed by depletion of LHRH production

Castration levels of testosterone and LH

Flare phenomenon, hot flashes, decreased libido, decreased potency,

weakness, emotional changes



250 mg PO tid

Nonsteroidal AA: Direct blockade of androgen receptor

Maintains serum testosterone level, libido, and potency

Diarrhea, changes in LFT results, gynecomastia, breast tenderness



150 mg PO qd

Nonsteroidal AA: direct blockade of androgen receptor

Maintains serum testosterone levels (once-daily dosing)

Alcohol intolerance,

abnormal light-to-dark adaptation,

interstitial pneumonitis



50 mg PO qd

Nonsteroidal AA

Maintains serum testosterone levels (once-daily dosing)

Breast tenderness,

gynecomastia, hot flashes, elevated LFT results



160 mg PO qd

Nonsteroidal AA

Maintains serum testosterone levels (once-daily dosing)


TERRAIN study supports use over bicalutamide in asymptomatic or mildly symptomatic metastatic CRPC (mCRPC) [14]


In patients with nonmetastatic CRPC, the PROSPER trial showed enzalutamide decreased risk for distant metastasis or death by 71% with a median metastasis-free survival of 36.6 compared with 14.7 months in the placebo group [15]


For metastatic CSPC, the ARCHES trial showed risk reduction of radiographic progression or death with enzalutamide plus ADT compared with placebo plus ADT (P < 0.001) [16]

Fatigue, back pain, hot flashes, risk of seizures


Avoid coadministration with strong CYP2C8 inhibitors


Induces CYP3A4 (strong), CYP2C9 (moderate), and CYP2C19 (moderate)


Posterior reversible encephalopathy syndrome (PRES) reported

Abiraterone acetate


1,000 mg PO qd

(given with prednisone 5 mg bid)

Steroidal AA: CYP17A1 inhibitor

Thought to reduce androgen levels within tumor tissue itself [17]


Approved for use in patients with mCRPC who have previously received chemotherapy containing docetaxel

Fatigue, hot flashes, hypokalemia, hypertension, edema


CYP3A4 substrate; avoid coadministration with strong CYP3A4 inhibitors

Cyproterone acetate

100 mg PO tid

Steroidal AA: Progestational activity inhibits LH release; also blocks androgen receptor

Prevents flare and hot flashes,

Lowers testosterone levels

Loss of libido and potency, possible cardiovascular toxicity,

risk of DVT, changes in LFT results

Degaralix (Firmagon)

Initial: 120 mg SC for 2 doses  (ie, 2 separate injections totaling 240 mg), THEN after 28 days, begin maintenance dose of 80 mg SC q28Days.


Gonadotropin-releasing hormone (GnRH) receptor antagonist; reduces LH and FSH production, ultimately decreasing testosterone production. Superior PSA progression-free survival; drug likely delays progression to castration-resistant disease. Flushing, injection site pain, weight gain, increase in serum transaminases
Relugolix (Orgovyx) GnRH receptor antagonist: Decreases gonadotropin release (ie, LH, FSH), thereby decreasing downstream production of testosterone by the testes  Oral administration; efficacy compares to leuprolide, but fewer adverse effects

Hot flashes, musculoskeletal pain

ADT may prolong QT/QTc interval



100 mg deep IM on days 1, 15, and 29, then q4wk for a total duration of 12wk

Gonadotropin-releasing hormone (GnRH) antagonist

Prevents flare,

Lowers testosterone levels

Potential immediate-onset, life-threatening allergic reaction;


Possible cardiovascular toxicity



1-5 mg PO qd

Hypothalamic/pituitary axis inhibitor

Castration levels of testosterone

Cardiovascular toxicity,

DVT, hot flashes, gynecomastia

AA=antiandrogen; CRPC=castration-resistant prostate cancer; CSPC=castration-sensitive prostate cancer; DVT=deep venous thrombosis; LFT=liver function tests; LH=luteinizing hormone; LHRH=luteinizing hormone–releasing hormone; PSA=prostate-specific antigen

In May 2010, the FDA stated that a preliminary and ongoing analysis found that men receiving gonadotropin-releasing hormone (GnRH) agonists were at a slightly increased risk for diabetes, heart attack, stroke, and sudden death. In October 2010, the FDA announced that prescribing information for GnRH agonists would include new warnings describing a small increase in risk for heart disease and diabetes. [18]

GnRH agonists approved in the United States include leuprolide (Eligard, Lupron, Viadur), nafarelin (Synarel), triptorelin (Trelstar), histrelin (Vantas), and goserelin (Zoladex). Nafarelin is approved only for the management of endometriosis; all others are approved for the treatment of advanced prostate cancer.


Selection of Candidates for NADT

High-risk patients (ie, those with a high T classification, Gleason score, or PSA level) with localized prostate carcinoma are likely to benefit most from effective neoadjuvant therapy. However, heterogeneous definitions of high-risk disease render trial-to-trial comparisons difficult. [12]

The use of preoperative nomograms that incorporate clinical T classification, serum PSA level, and biopsy Gleason grade can enhance prediction of the risk of PSA recurrence and selection of a relatively homogeneous population. The percentage of cancer in biopsy cores and the number of positive biopsy cores, as well as the incorporation of biomarkers (eg, serum interleukin 6 [IL-6]–soluble receptor and transforming growth factor beta-1), may further improve predictive accuracy. [19]

Although a relatively high threshold of PSA recurrence to determine eligibility is reasonable, it may negatively affect accrual. In addition, investigators may determine that radiotherapy, instead of prostatectomy, is the optimal treatment in such high-risk patients. Conversely, setting a lower threshold of recurrence may result in unnecessary treatment, a reduction in the event rate, and an increase in the number of patients required.

It may be reasonable to hypothesize that patients with a relatively high risk of recurrence may be optimal candidates for cytotoxic chemotherapy, whereas those with a lower risk of recurrence may be optimal candidates for more tolerable biologic agents and immunotherapy.


Clinical Trials of NADT

Nonrandomized trials (stage T1-T3)

Many nonrandomized trials of neoadjuvant androgen deprivation therapy (NADT) have been conducted in patients with clinical stage T1-T3 disease (see Table 2, below). For example, Fair et al reported a nonrandomized study of 3 months of NADT with a luteinizing hormone–releasing hormone (LHRH) agonist and flutamide in 69 patients with T1-T3 prostate cancer, using 72 stage-matched controls. [20] Results in the NADT arm versus the control arm were as follows:

  • Pathologic organ-confined rate: 74% versus 48%
  • Margin-positive rate:10% versus 33%
  • Prostate-specific antigen (PSA) disease-free rate at a mean follow-up of 28.6 months: 89% versus 84%

No significant difference between the treatment arm and the control arm was seen with respect to biochemical failure.

Meyer et al reported on 38 months of follow-up in 680 patients, 292 of whom received NADT prior to radical retropubic prostatectomy, [21] and the rates of positive surgical margins were lower in the NADT group than in the prostatectomy-only group (25% vs 47%, respectively). Patients treated with NADT had significantly lower hemoglobin and hematocrit levels before surgery and, therefore, required blood transfusion more often. No difference in risk of PSA failure (> 0.3 ng/mL) was observed overall between the hormone-therapy and prostatectomy-only groups. However, patients receiving combined therapy for more than 3 months had a significantly lower risk of PSA failure than those treated with radical prostatectomy (RP) alone, suggesting a possible benefit in terms of disease-free survival.

In one of the largest nonrandomized, retrospective reviews of NADT, conducted at the University of Miami, patients who received NADT were less likely to have positive margins (28% vs 38%). In the study, of 546 consecutive patients undergoing RP, 135 received NADT for a median duration of 3 months prior to surgery. In an effort to create 2 comparable groups among those who did or did not receive NADT, only patients with a PSA value of greater than 10 ng/mL and/or a Gleason score of greater than 7 and/or a stage greater than cT2b were included in the analysis.

The impact of NADT on pathologic outcome and disease recurrence was assessed for a mean follow-up of 26 months. The incidence of extracapsular extension, seminal vesicle invasion, and lymph node metastasis was no different between the 2 groups. The recurrence rate was 17% in nontreated patients and 25% in treated patients. Even though a lower incidence of positive surgical margins was observed in the NADT arm, the difference did not translate into improved disease-free survival at 26 months of follow-up.

In 2009, Gao et al conducted a retrospective study evaluating 31 patients with local prostate carcinoma who underwent RP and found that the incidence of positive surgical margins, seminal vesicle invasion, and lymph node metastasis was lower in the group who underwent NADT (n = 12) than in the RP-only group (n = 19). Hormonal deprivation was carried out using a combination of goserelin and flutamide for 5.6 months. [22]

Many studies have also shown that there may be a delay to biochemical recurrence and improvement in surgical margins in high-risk patients who undergo NADT. See Table 2, below. However, limitations to these studies have been small sample size, no standardized definition of "high risk", short follow-ups, and no statistical significance in overall survival benefit. [23, 24, 25, 26, 27]

Table 2. Nonrandomized Trials of Neoadjuvant Androgen Deprivation Therapy (Open Table in a new window)


Number of Patients

Clinical Stage

NADT Type and Duration

(mo )

PSA Reduction


Positive Margins


Seminal Vesicle Invasion


Lymph Node Metastasis




Soloway et al, 1994 [28]



TAB*, 3-16






Fair et al, 1993 [20]



DES, 2-8




Solomon et al [29]



TAB, 3-6



Schulman and Sassine [30]



TAB, 2-12



Pummer et al [31]



TAB, 3-6






Haggman et al [32]



TAB, 3





Oesterling, Andrews,

Suman et al [33]



TAB, 1-4






Macfarlane et al [34]



TAB, 3






Abbas et al [35]



TAB, 3-20






Gleave et al [36]



TAB, 8





Meyer et al [21]



TAB, 3





Soloway et al, 2002 [23]



TAB, 3





Gao et al [22]



TAB, 5.6 (3-8)


NAD 25

RP 43

NAD 8.3 RP 21

NAD 8.3

RP 15.8


*Total androgen blockade


Randomized trials

LHRH agonist and flutamide

Multiple randomized trials of NADT have been conducted. See Table 3, below.

Table 3. Randomized Clinical Trials of Neoadjuvant Androgen Deprivation Therapy (Open Table in a new window)


Number of Patients

Clinical Stage

NADT Type and Duration (mo)

Organ-Confined Disease (%)

Positive Margins (%)

Seminal Vesicle Invasion (%)

Lymph Node Metastasis (%)

Mean Follow-Up (mo)

Labrie et al [37]



LHRH agonist and flutamide, 3

77 NAD

34 RP

13 NAD

38 RP

12 NAD

34 RP


6 RP


Debruyne et al [38]


T2-T3, N0M0

LHRH agonist and flutamide, 3

27 NAD

39 RP


Soloway et al [39]


T2b, N0M0

LHRH agonist and flutamide, 3

53 NAD

22 RP

18 NAD

48 RP

15 NAD

22 RP


6 RP


Goldenberg et al [40]



Cyproterone acetate, 3

34 NAD

64 RP


Van Poppel et al [41]



Estramustine, 6

72 NAD

63 RP

58 NAD

53 RP


Witjes et al [42]



LHRH agonist and flutamide, 3

71 NAD

51 RP

27 NAD

46 RP


3 RP


Aus et al [43]



LHRH agonist and cyproterone acetate, 3

24 NAD

45 RP

14 NAD

22 RP


14 RP


Prezioso et al [44]



LHRH agonist and cyproterone, 3

39 NAD

60 RP


11 RP

Dalkin et al [45] 56 T1c-T2b LHRH agonist, 3

57 NAD

61 RP

18 NAD

14 RP



4 RP

Selli et al [46] 393 T2-3, N0M0 LHRH agonist, 3 or 6


26 NAD x 3 mo

19 NAD x 6 mo

47 RP

... ... ...
van der Kwast et al [47] 40 T1-T3 LHRH agonist or leuprolide with flutamide, 3 or 6 ...

28 NAD x 3 mo

9 NAD x 6 mo

11 NAD x 3 mo

5 NAD x 6 mo

... ...
Yee et al [25] 148 T1-T3 LHRH agonist and flutamide, 3

85 NAD

80 RP

19 NAD

38 RP


6 RP


3 RP


In the first prospective, randomized trial of NADT, Labrie et al randomized 142 men with stage B0-C2 cancer to surgery alone or to 3 months of an LHRH agonist and flutamide followed by RP and reported significant clinical and pathologic down-staging and a decreased incidence of positive margins, seminal vesicle invasion, and lymph node metastasis in the NADT group. No follow-up was reported. [37]

In a multicenter trial by Soloway et al, patients with T2bN0M0 prostate cancer were randomized to RP plus NADT with an LHRH agonist and flutamide (149 patients) or surgery alone (154 patients), and patients who received androgen deprivation preoperatively were found to have significantly lower rates of capsule penetration (47% vs 78%), positive surgical margins (18% vs 48%), and tumor at the urethral margin (6% vs 17%). [39]

In that study, androgen deprivation did not affect seminal vesicle invasion or lymph node metastasis. Prostate volume decreased by 30%, and the PSA level decreased to less than 1 ng/mL in 88% of patients and to less than 2 ng/mL overall. Upon pathologic examination, no evidence of tumor (pT0) was found in 6 (4%) patients treated with NADT. However, at 42 months of follow-up, no significant difference in recurrence (25%) was noted between the 2 groups. [39]

In a large randomized trial by Witjes et al (European Study Group on Neoadjuvant Treatment of Prostate Cancer) that included 354 patients, of whom 164 were treated with NADT (goserelin acetate plus flutamide) for 3 months, serum PSA levels decreased by more than 90% in the NADT group. Pathologic down-staging was observed in 16% of the NADT group and 6% in the surgery-alone group. Positive margins were significantly less frequent in NADT patients with clinical T2 tumors, but there was no difference in those with clinical T3 tumors. At 15 months of follow-up of 215 patients, the progression-free survival rate did not differ between the 2 groups. The researchers concluded that neoadjuvant therapy was investigational and not advisable outside of randomized clinical trials. [42]

Enzalutamide and bicalutamide

Enzalutamide proved superior to bicalutamide in the TERRAIN clinical trial, a double-blind, randomized phase II study in 375 asymptomatic or minimally symptomatic men with prostate cancer progression on ADT. Median progression-free survival was significantly longer with enzalutamide than bicalutamide (15.7 versus 5.8 months; hazard ratio [HR], 0.44; P< 0.0001). However, 68% of patients in the enzalutamide group and 88% of those in the bicalutamide group discontinued their assigned treatment before study end, mainly due to progressive disease. [14]

Intense Androgen Deprivation Therapy

McKay et al conducted a multicenter trial randomizing 75 patients with biopsy Gleason score of 4 + 3 = 7 or higher into either enzalutamide and leuprolide (EL) alone or enzalutamide, leuprolide, abiraterone, and prednisone (ELAP) groups. More patients treated with ELAP therapy had a complete response or minimal residual disease compared with the group that received EL alone (30% vs. 16%). While a pathologically favored response was noted, the results between both treatment arms was not statistically significant. Correlation with long-term outcomes is warranted at this time. [48]  


Relugolix is the first oral androgen deprivation therapy approved by the FDA for advanced prostate cancer. It is a gonadotrophin-releasing hormone (GnRH) receptor antagonist that decreases gonadotropin release (ie, luteinizing hormone, follicle stimulating hormone), thereby decreasing the downstream production of testosterone by the testes. 

Approval of relugolix was based on the HERO clinical trial (n = 622). In HERO, sustained testosterone suppression at 48 weeks was achieved in 96.7% of relugolix-treated patients compared with 88.8% with leuprolide. Risk of major adverse cardiovascular events was 54% lower with oral relugolix compared with leuprolide injections. [49]

Cyproterone acetate

The Canadian Urologic Oncology Group published the results of a randomized study on 213 patients, of whom 112 were treated with 12 weeks of cyproterone acetate 300 mg daily prior to surgical therapy. In the NADT group, the volume of the prostate gland, determined by transrectal ultrasonography, decreased by 20% and the incidence of positive margins was lower than in the surgery-only group (27.7% vs 64.8%). Both groups were well balanced at baseline in terms of demographics, clinical stage, Gleason score, PSA value, and prostate size. No tumors were down-staged to pT0. However, at 36 months of follow-up, no difference was noted in the biochemical recurrence rate. [40]

Prezioso et al randomized 167 patients with localized prostate cancer to receive either leuprolide acetate depot 3.75 mg once a month for 3 months and cyproterone acetate 300 mg once a week for 3 weeks prior to surgery (group A) or no pretreatment before surgery (group B), and found that in group A, tumor/prostate volume decreased in 31% of patients after hormone therapy and that PSA and testosterone levels fell significantly from basal values. Positive surgical margins (60% vs 39%) and lymph node involvement (11% vs 3%) were more common in group B than in group A. [44]

Epidermal growth factor receptor

Epidermal growth factor receptor (EGFR) has been implicated in prostate cancer growth. In a randomized, prospective, controlled, intention-to-treat study in 119 patients with clinical stage T2-T3 prostate cancer, Gravina et al investigated the ability of NADT with bicalutamide to reduce positive surgical margins and modulate EGFR, and discovered that the 61 men who received bicalutamide, 150 mg daily for 120 days before RP, had a 3.5-fold increase in negative surgical margins. [50]

In the study, Gravina and colleagues also found that in stage pT3a tumors, negative surgical margins increased 5-fold in patients who underwent bicalutamide treatment. In patients with stage pT2 tumors, the investigators found no difference for this surgical outcome. However, immunohistochemical analysis revealed that early after bicalutamide treatment, EGFR levels increased 2.8-fold and levels of the Her2/neu oncogene were upregulated 2.7-fold. The investigators speculated that the capacity of the residual tumor to acquire compensatory survival pathways may overwhelm the benefits of NADT. [50]


Overall and Disease-Free Survival

A systematic review and meta-analysis of neoadjuvant androgen deprivation therapy (NADT) in localized or locally advanced prostate cancer (stages T1-T4, any N, M0) by Kumar et al showed that NADT did not improve overall survival. [51]

However, NAD did produce a significant reduction in the positive surgical margin rate and a significant improvement in other pathologic variables, such as lymph node involvement, pathologic staging, and organ-confined rates. There was a borderline significant reduction of disease recurrence rates. Although these latter outcomes were of secondary importance to overall survival, the significant benefit achieved with these pathologic variables suggests that NADT may be useful in attaining local control in nonmetastatic prostate cancer. [51]

Three other studies also provided information on overall survival. With a 4-year follow-up period, Schulman et al reported no difference in overall survival rates with NADT plus radical prostatectomy (RP) compared with RP alone (93% vs 95% of patients alive in the treatment and control groups, respectively). [52]

Similarly, Klotz et al reported no difference in overall survival with NADT (88.4% vs 93.9% of patients alive in the treatment and control groups, respectively). [24] Finally, Aus et al found no significant difference in overall survival with NADT after 7 years of follow-up. [53]

Those 3 studies showed that giving hormone therapy before prostatectomy does not provide a significant survival advantage over prostatectomy alone. Studies that have analyzed disease-free survival (defined by either biochemical or clinical progression) have also shown no statistically significant difference with NADT. In the study with the longest follow-up, conducted by Aus et al, PSA progression–free survival over 7 years was 49.8% in the neoadjuvant arm and 51.5% in the prostatectomy arm. [53]

Similarly, Klotz et al found that 5-year biochemical disease-free survival was 60.2% and 68.2%, respectively, for the NADT and surgery-only arms. [24] Soloway et al reported a 5-year biochemical-free survival of 64.8% for the hormonal arm, versus 67.6% for the surgery-only arm, in patients with clinical stage T2 disease. [23] Schulman et al found that the 4-year PSA progression rates of patients with T2-T3, NO, MO disease in the NADT and the surgery-only arms were 26% and 33%, respectively. [52]


Histopathologic Changes in NADT

Androgen deprivation therapy produces distinct histopathologic changes in neoplastic and nonneoplastic prostate tissue. A pathologist who is not familiar with these alterations may misinterpret the specimen, resulting in inappropriate tumor grading or missed tumor foci. Thus, the urologist should convey to the pathologist any information regarding therapy that might cause histopathologic changes.

Civantos et al published the largest series on the pathology of androgen deprivation therapy for prostate cancer, and in the series of 173 patients who were treated with a luteinizing hormone-releasing hormone (LHRH) analogue and an antiandrogen (AA) prior to radical prostatectomy (RP), atrophy was observed in benign and malignant tissue. Examination of noncancerous tissue revealed atrophy of secretory cells, with cytoplasmic clearing and vacuolization. Atrophy and disappearance of luminal cells resulted in basal cell prominence. Morphologic alterations induced by treatment were patchy; the entire neoplastic tissue was affected in only 57% of the specimens. The poorly differentiated areas of tumors were affected less frequently. [54]

Three types of changes in neoplastic tissue were reported in the Civantos study [54] :

  • In the most common pattern (90%), the size of the neoplastic glands was reduced; an increase in stroma with a resultant relative decrease in gland density accompanied the size reduction

  • Branching, empty spaces lined by a few remaining cancer cells with pyknotic nuclei and foamy vacuolated cytoplasm characterized the second pattern (20%)

  • The third pattern (10%) consisted of large, clear, or vacuolated tumor cells within an inflammatory background; the incidence of high-grade prostatic intraepithelial neoplasia was less common in the prostate specimens from patients treated with neoadjuvant therapy.


Pathologic Implications of NADT

Reduction in positive-margin rate

Clinical trials have demonstrated that neoadjuvant androgen deprivation therapy (NADT) significantly reduces the rate of positive surgical margins, owing to either tumor regression or the improved ability to resect the prostate with wider surgical margins.

The interpretation of margin status on radical prostatectomy (RP) specimens after NADT has been the source of much debate. However, the authors believe that with the use of consistent step-sectioning and special stains, an experienced uropathologist can identify a true positive margin accurately. The effectiveness of NADT in reducing positive surgical margins depends on clinical tumor stage and the biopsy Gleason score.

NADT has been demonstrated to decrease positive margins significantly in clinical stage T1 and T2 prostate cancer. Men with cT3 disease or a Gleason score greater than 7 have a less dramatic reduction in positive margins, implying that higher-grade tumors may be less responsive to NADT.

Improvement in pathologic variables

Treatment with neoadjuvant hormones has been shown to substantially improve local pathologic variables, such as organ-confined rates, pathologic down-staging, and rate of lymph node involvement. With regard to seminal vesical invasion, one study reported a decrease in seminal vesicle invasion rate with neoadjuvant therapy, [23] whereas another study showed no difference. [24]

Changes in Gleason criteria

Two of the Gleason criteria are altered by NADT. A decrease in gland size and an increase in stroma between glands occur. These findings can lead to a false upgrade of the Gleason score. The use of a modified Gleason system has been proposed to evaluate prostatectomy specimens from patients who have received NADT; some physicians have suggested that no Gleason score should be allocated.


Surgical Implications of NADT

Neoadjuvant androgen deprivation therapy (NADT) has been demonstrated to decrease prostate volume by 20-50%. The initial hope was that shrinking the gland would make radical prostatectomy (RP) technically easier, with less blood loss. The findings in this regard have been inconsistent.

In the multicenter, randomized T2bN0M0 trial, surgeons rated the difficulty of dissection, presence of seminal vesicle adherence, and extent of blood loss and found that seminal vesicle adherence to the periprostatic tissues was more common in patients pretreated with NADT (37%) than in those treated with surgery alone (21%). They also recorded the operating time and amount of blood transfused. Surgical dissection was more difficult in pretreated patients. No significant difference in operating time, blood loss, or transfusion requirement occurred.

Although more dissections that were difficult were reported with NADT in this study, no operative complications occurred in the NADT group, whereas 6 intraoperative injuries were reported in patients who underwent surgery alone.

In patients with large prostates, NADT may facilitate resection by reducing prostate volume, creating more space for the surgeon to operate. However, in patients with smaller prostates, NADT may have a less-desirable effect by allowing the prostate to recede farther under the pubic bone, complicating exposure during the apical dissection. The periprostatic fibrous reaction is variable and may increase the difficulty of surgery, particularly at the apex and seminal vesicles.

The authors believe that interference with apical dissection is potentially the most difficult problem caused by NADT. Also of serious concern is the fact that NADT-induced fibrosis can make intraoperative evaluation of the extent of the tumor more difficult, which in turn may compromise the extent of resection if the surgeon relies on intraoperative findings to determine performance of a nerve-sparing operation.


Duration of NADT

The optimal duration of neoadjuvant androgen deprivation therapy (NADT) prior to radical prostatectomy (RP) is unknown. Most trials have arbitrarily used 3 months of therapy. However, some evidence indicates that a longer duration of NADT could provide greater surgical down-staging.

Gleave et al showed a significant improvement with 8 months neoadjuvant therapy compared with 3 months. They attributed the initial dramatic fall in prostate-specific antigen (PSA) values caused by androgen ablation to the cessation of androgen-regulated PSA gene expression, whereas a continuing gradual decline represented the actual decrease in tumor volume. The mean PSA level in study patients decreased 84% after 1 month, with a further decrease of 52% from 3-8 months. In 22% of patients, the PSA reached its nadir at 3 months; in 84% of patients, after 8 months. Therefore, these authors advocated 8 months as the optimal duration of treatment. [55]

Two other studies have compared 3 versus 6 months of neoadjuvant therapy, showing a trend toward an improvement in positive surgical margin rates with 6-month therapy. [46, 47]

A meta-analysis of the 3 comparative studies showed a significant improvement in the positive surgical margin rates in favor of the longer treatment duration (6 or 8 months). [51]

In contrast, Pu et al found no significant difference in rates of positive surgical margin between men treated with 3 months of NADT and those treated with 8 months. However, the positive margin rate was significantly lower in men who received either 3 or 8 months of NADT than in a third group, who did not receive NADT.

In the study, there were no significant differences in the 3 groups with respect to mean operative time, mean blood loss, transfusion rate, operative difficulty, catheterization time, hospital time, and complication rate. In the patients who received 8 months of NADT, the mean prostate volume was significantly smaller after 8 months than after 3 months; serum PSA values decreased by 98.1% after 3 months and showed a further 72.9% decline after 8 months. [56]

A meta-analysis by Kishan et al concluded that the addition of androgen deprivation therapy to radiotherapy significantly improved metastasis-free survival, as did prolongation of adjuvant therapy from 4-6 months to 18-36 months. However, extension of NADT from 3-4 months to 6-9 months did not produce significant improvement. The meta-analysis included 12 randomized trials that provided individual patient data (10,853 patients) with a median follow-up of 11.4 years. [57]


Advantages and Disadvantages of NADT

Neoadjuvant androgen deprivation (NADT) offers the following potential advantages:

  • Rate of positive margins is reduced
  • Organ-confined disease is increased
  • Serum PSA level is reduced
  • Prostate size is reduced.

The following disadvantages of NADT have been identified:

  • Clinical trials have not demonstrated unequivocal improvement in disease-free survival rates
  • NADT has an unknown therapeutic effect on microscopic local or metastatic disease
  • Poorly differentiated areas of tumor are altered minimally
  • Tumor is rarely completely eradicated (pT0)
  • Risk of androgen-independent clonal proliferation exists with prolonged NADT
  • Ability to evaluate the extent of the tumor at surgical resection may be compromised
  • Pathologic interpretation may be obscured
  • Increased difficulty occurs at surgery due to periprostatic fibrosis
  • Cost of therapy is a disadvantage
  • Adverse effects are a potential disadvantage
  • Treatment of the tumor is delayed
  • Likelihood of requiring blood transfusion during surgery is increased

Combining NADT and Chemotherapy

Pan et al conducted a retrospective review of 3 different therapies in patients with very-high-risk localized prostate cancer: (i) neoadjuvant chemohormonal therapy (NCHT), in 60 men; (ii) neoadjuvant hormonal therapy (NHT), in 73 men; and (iii) immediate RP without neoadjuvant therapy (No-NT), in 44 men. The NCHT group had better biochemical progression-free survival (bPFS) time after surgery compared with the NHT and No-NT groups (19 vs 13 vs 9 months, respectively). After RP, 81% (42/52) of patients in NCHT group, 73% (51/70) of patients in NHT group, and 48% (21/44) of patients in No-NT group achieved an undetectable PSA (P < 0.001), despite patients in the NCHT having significantly poorer prognostic factors. Randomized controlled investigations are needed to validate these results, and further follow-up is required. [58]

Multiple phase I/II trials have also been performed to investigate the use of neoadjuvant chemotherapy alone prior to RP, however no patients in these trials achieved a complete pathologic response (pT0). [59] As there is currently no evidence demonstrating improved clinical outcomes with the use of neoadjuvant chemotherapy alone or neoadjuvant androgen deprivation therapy (NADT) alone, future research will likely focus on combined neoadjuvant chemohormonal therapy. [60]  

A few phase I/II trials have investigated the use of neoadjuvant targeted therapies, which inhibit receptors such as the platelet-derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR), and vascular endothelial growth factor receptor (VEGF). None, however, have shown a significant improvement in pathologic or clinical outcomes. [61]

Although no data have yet emerged that definitively support the routine use of neoadjuvant chemohormonal therapy, its safety has been evidenced by several phase I/II clinical trials. Most of the trials on neoadjuvant chemohormonal therapy have investigated docetaxel. These are summarized in Table 4 below. 

Table 4. Phase I/II clinical trials on docetaxel-based neoadjuvant chemohormonal therapy (Open Table in a new window)

First Author Year Number of Patients Docetaxel Dosing Additional NADT Agents NADT Duration (weeks) Pathologic Complete Response (%) Positive Surgical Margins (%) Progression-free Survival (%) Median Follow-up (mo)
Prayer-Galetti [62] 2007 22 q3 weeks, 4 cycles Luteinizing hormone–releasing hormone (LHRH) agonist, Estramustine 12 5 26 42 53 
Chi [63] 2008 72 6 weekly doses, 2 off, 3 cycles LHRH agonist, Flutamide/bicalutamide 24 3 27 70 42
Sella [64] 2008 22 q3 weeks, 4 cycles LHRH agonist, Estramustine, bicalutamide 12 0 27 54 23
Mellado  [65] 2009 57 q3 weeks, 1 off, 4 cycles LHRH agonist, Flutamide 12 6 35 65 35
Womble  [66] 2011 22 q3 weeks, 4 cycles Ketoconazole 12 0 42 36 18
Narita  [67] 2012 18 6 weekly doses, 1 cycle LHRH agonist, Estramustine, bicalutamide 6 11 0 77 18
Thalgott  [68] 2014 30 q3 weeks, 3 cycles LHRH agonist, Bicalutamide 9 0 43 55 49
Eastham [9] 2020 391 q3 weeks, 6 cycles LHRH agonist 18-24 0 18 81 73

Prayer-Galetti et al

Prayer-Galetti et al, in evaluating 22 patients with high-risk prostate cancer who underwent neoadjuvant treatment combining a luteinizing hormone–releasing hormone (LHRH) analogue, estramustine, and docetaxel before undergoing radical retropubic prostatectomy, found that 3 patients (14%) had a clinical complete response and that 17 (81%) a partial response. One patient with sarcomatoid tumor had local progression after chemotherapy The neoadjuvant treatment was well tolerated, with only one case of grade 2 toxicity (Eastern Cooperative Oncology Group grading). After chemotherapy, all patients had a PSA level of 0.6 ng/mL or less (mean, 0.17 ng/mL), and the reduction from before to after chemotherapy was statistically significant. [62]

Of the 19 patients who underwent radical retropubic prostatectomy, the pathologic organ-confined disease rate was 58%. The mean predicted likelihood of organ-confined disease in these patients, according to the Kattan nomogram, was 8%. One (5%) patient had a pathologic complete response (pT0), and in 6 patients, the residual tumor was confined to small foci (< 10% of the prostate volume) and was composed of single cells or small groups of tumor glands. Comparing pathologic and clinical stages, the down-staging rate was 42% (8 patients).

Five patients (26%) had positive surgical margins, and 4 (21%) had positive lymph nodes. At a median follow-up of 53 months (range, 30–64 mo), 8 patients (42%) remained disease-free, 9 (47%) had biochemical recurrence, and 2 (11%) had local recurrence. [62]

Chi et al

Chi et al, in a phase II, multicenter study of NADT (6.3 mg buserelin acetate every 8wk for 3 doses and antiandrogen for 4wk) with docetaxel (35 mg/m2 intravenously, weekly for 6 consecutive weeks, followed by a 2-week rest for 3 cycles) in newly diagnosed patients with untreated, clinically localized prostate cancer and high-risk features, found that 2 patients (3%) had a pathologic complete response and that 18 patients (28%) had 5% tumor volume in the prostatectomy specimen. [63]

Four patients in the study discontinued therapy because of toxicity, including 2 who suffered severe hypersensitivity reactions and 2 who developed pneumonitis (grades 3 and 4). Seventeen patients (27%) had positive surgical margins, and 4 were found to have involvement of regional lymph nodes. After a median follow-up of 42.7 months, 19 recurrences (30%) occurred.

Sella et al

Likewise, Sella et al, in a trial of neoadjuvant chemohormonal therapy and RP in patients with poor-prognosis, localized prostate cancer (PSA level ≥20ng/mL, Gleason score ≥8, clinical stage ≥T2c), found that at a median follow-up of 23.6 months (range, 12.1-54.7mo), disease relapsed in 10 patients (45.4%). [64]

The surgical specimens in relapsed cases revealed positive surgical margins in 5 (50%), capsular invasion in 6 (60%), and both in 8 (80%). Viable disease was detected in all patients. The pathologic organ-confined disease rate was 63.6% (14 patients). The specimen-confined disease rate was 72.7% (16 patients). In 9 patients (40.9%), the tumor involved the seminal vesicles. In 4 patients (18.1%), the disease disseminated to the pelvic nodes, and in 9 patients (40%), the tumor invaded the perineural area.

No correlation in the study was found between nerve sparing (1 or 2 nerves) or specimen/organ-confined status and relapse, showing that a neoadjuvant chemohormonal approach with nerve-preservation surgery is feasible in patients with poor-prognosis localized prostate cancer.

Konety et al

The phase I/II trial on neoadjuvant chemohormonal therapy by Konety et al is the one with the longest follow-up. In this trial, 36 patients received 4 cycles of paclitaxelcarboplatin, and estramustine plus goserelin acetate before radical prostatectomy (RP), with the clinical stage being reduced in 39% of patients. Deep venous thrombosis (DVT) occurred in 22% of patients. The positive margin rate was 22%, and 45% of the patients remained free from PSA recurrence after a median follow-up of 29 months. [69]

In an update to this trial, with a median follow-up of 13.1 years, most patients developed biochemical recurrence (BCR) within 10 years (BCR-free probability 22%; 95% confidence index [CI] 10-37%). The probability of disease-specific survival, however, was 84% (95% CI 66-93%) at 10 years, and overall survival was 78% (95% CI 60-89%). [70]

Pettaway et al

Pettaway et al recruited 33 high-risk patients in a phase II trial and administered 12 weeks of ketoconazole plus doxorubicin alternating with vinblastineestramustine, and combination androgen deprivation therapy followed by prostatectomy. All patients achieved an undetectable PSA value postoperatively. Moreover, 20 of 29 patients were free of recurrence after a median follow-up of 13 months. Manageable postoperative complications occurred in 33% of patients. Of 30 patients, 33% had organ-confined disease, 70% had extraprostatic extension, 37% had positive lymph nodes, and 17% exhibited positive surgical margins. [71]

Hussain et al

Because estramustine phosphate (EMP) induces biochemical castration through its estrogenic activity, it may be appropriate to consider estramustine-containing chemotherapy as a subcategory of chemohormonal therapy. Generally, EMP-based chemotherapy has been abandoned because of toxicities, especially thromboembolism.

Neoadjuvant EMP resulted in a significant decrease in positive surgical margins in patients with T2b disease in a randomized trial. Hussain et al treated 21 patients with 3-6 cycles of docetaxel plus EMP followed by radiation or prostatectomy (10 patients underwent prostatectomy, and 11 patients underwent radiotherapy). Of the 10 patients who underwent prostatectomy, 7 patients had negative surgical margins, while 2 of the 11 patients who received radiation displayed negative preradiotherapy biopsy results. At a median follow-up of 13.1 months, 71% of all patients showed no evidence of disease. [72]

Clark et al

Clark et al evaluated 3 cycles of EMP plus etoposide before RP in 18 patients with locally advanced disease, and all patients achieved an undetectable PSA level postoperatively. Five patients (28%) experienced grade 3 toxicity (2 with DVT, 2 with neutropenia, and 1 with diarrhea), and 1 patient (6%) experienced grade 4 toxicity (pulmonary embolus) before surgery. Organ-confined disease was observed in 31% of patients, and residual carcinoma with androgen-deprivation effect was observed universally. Nine patients (56%) had specimen-confined disease. [73]

Eastham et al

A phase III clinical trial by Eastham et al in patients with high-risk clinically localized prostate cancer compared biochemical progression-free survival (BPFS) in 391 patients who received NADT with leuprolide or goserelin for 18-24 weeks plus a median of 6 cycles of docetaxel. No difference was found in the primary study end point, 3-year BPFS (0.89 vs 0.84, respectively; 95% CI for the difference, −0.01 to 0.11; P = 0.11. Rates of 5-year BPFS and prostate cancer–specific survival between the treatment groups were also comparable. NADT did produce improvement in the secondary end points of overall biochemical progression–free survival, metastasis-free survival, and overall survival. However, the authors concluded that the study results do not support the routine use of NADT prior to RP in patients with clinically localized, high-risk prostate cancer. [9]