Public Release: 

New treatment options for patients with prostate cancer

ECCO-the European CanCer Organisation

Paris, France, Monday 31 October 2005 - New findings on different treatment options including new therapies for prostate cancer were presented at the 13th European Cancer Conference (ECCO).

A Dutch study suggested treating prostate cancer patients with higher doses of radiotherapy significantly improved patient outcome and treatment over a five-year period. Another evaluated which patients would benefit from early adjuvant anti-androgen therapy. Data was presented on a new compound to treat androgen independent prostate cancer. An Australasian study reviewed the benefits of administering maximal androgen deprivation treatment before radiotherapy.

The Dutch study, a multicentre randomised Phase III trial, recruited 669 patients with stage T1b-T4N0M0 (free from cancer in the lymph nodes and no metastasis has occurred) prostate cancer and with baseline characteristics of median PSA (prostate specific antigen) of 13.0ng/ml. 63% of patients had T1-2 tumours (smaller tumours localised to the prostate). Patients were divided into three prognostic groups of low, intermediate and high risk which included 18%, 27% and 55% of patients respectively. These groups were treated with either the higher dose of radiotherapy at 78Gy or the conventional dose at 68Gy. Some of the patients from the intermediate and high risk groups were also receiving hormonal therapy (143 in total).

The aim of the study was to determine whether the higher dose of radiotherapy, 78Gy, offered more effective treatment of prostate cancer than the conventional dose at 68Gy. The study's endpoint was defined as 'freedom from failure' or clinical failure (clinical relapse or start of hormone treatment).

Results indicated at five years, that 'freedom from failure' was significantly improved in patients receiving the 78Gy radiotherapy dose than those receiving the 68Gy dose. The intermediate risk patients experienced the most benefit from the higher dose treatment (74% vs 58%. p=0.03). The gain in the high risk group was smaller (52% vs 44%, p=0.1) and there was no benefit in the low risk group (84% vs 86%, p=0.7). In overall data terms, there were no significant differences in overall survival (83% vs 82%) and 'freedom from clinical failure' (76% vs 76%) between the two radiotherapy doses.

Speaking on behalf of the study authors at the Netherlands Cancer Institute in Amsterdam, Professor Harry Bartelink commented, "This trial demonstrated that for radiotherapy of prostate cancer patients, higher radiation doses are more effective than conventional doses, and that these doses can be delivered safely. The consequence of this first analysis trial is that the standard treatment for prostate cancer should change to a higher radiation dose, as we predict that a higher local control rate will be obtained and eventually, a higher survival rate."

In the largest hormone therapy trial, the Early Prostate Cancer programme (EPC), ever conducted in prostate cancer patients, results indicated which patients would benefit from early anti-androgen therapy over a period of seven years. Patients (8113 in total) selected were diagnosed with localised (T1-2, N0/Nx) or locally advanced (T3-4, any N; or any T, N+) prostate cancer (all M0). Patients received bicalutamide (anti-androgen) or placebo once daily plus standard care (radiotherapy, radical prostatectomy surgery or watchful waiting - see if tumour progresses or stays the same without treatment). Primary endpoints were overall survival (OS) and objective progression-free survival (PFS).

The data revealed that in localised disease, there was no significant PFS or OS benefit but in locally advanced disease, bicalutamide significantly improved OS in patients in combination with radiotherapy. Additionally bicalutamide produced a trend towards improved OS in patients with locally advanced disease who would have otherwise undergone 'watchful waiting'. However no overall survival benefit was achieved in patients who had surgery - radical prostatectomy.

Speaking about his study findings, Professor Peter Iversen stated, "Results from the EPC Trial Programme provide a significant step forward in our understanding of which men with early non metastatic prostate cancer benefit from the addition of bicalutamide 150mg therapy, enabling physicians to be more targeted in their selection of appropriate treatments. These data show that men with localised disease gain no significant benefit while men with locally advanced disease derive significant benefit from addition of bicalutamide therapy."

In an ongoing study, a new immunotherapy product, APC8015, is currently under investigation for the treatment of non-hormone responsive or androgen independent prostate cancer (AIPC). Preliminary results have been released from one of the two Phase III trials which demonstrated a significant survival for APC8015 treated patients in the intent-to-treat group compared with placebo. Results from the other clinical trial will be reported later and may confirm and strengthen the data found from the first trial.

Study author, Dr Tia Higano from The University of Washington, USA commented, "The combined data from these trials of APC8015 versus placebo suggest that immunotherapy might impact survival in men with androgen independent prostate cancer. APC8015 has a favorable safety profile. Future studies in patients with earlier stage disease or in combination with other agents will be of great interest."

The Australasian study determined whether 3 or 6 months maximal androgen deprivation (MAD) administered prior to and during radiotherapy improved treatment outcomes for patients with locally advanced prostate cancer. 818 patients, between June 1996 and February 2000, were randomised at 19 Australian and New Zealand centres to receive radiotherapy alone or MAD treatment either starting at 3 or 6 months before radiotherapy. Their cancers were staged at T2bc, T3 and T4 (N0, M0).

Improvements in various outcome measures were observed with 3 months MAD treatment prior to radiotherapy; in reduced local failure, improved biochemical failure free survival, clinical disease free survival and freedom from salvage therapy. The 6 month MAD treatment prior to radiotherapy improved on these effects and also reduced distant failure and produced significant improvement in cause specific survival. The investigators added that patients with 'high risk' cancer also experienced a strong trend towards improved overall survival. They concluded that further follow up studies were needed to estimate the size of survival benefits precisely.

About Prostate Cancer

The prostate is a small gland about the size and shape of a walnut situated just below the bladder and surrounding the urethra. The prostate produces the seminal fluid in which sperm is transported. Prostate cancer begins with small changes in size and shape of the prostate gland cells which can develop into an uncontrolled growth of cells.

Prostate cancer predominantly affects Western populations although the black population has a significantly higher rate than the white population. The lowest incidence is seen in Asian populations.1There are just under 238,000 cases of prostate cancer in Europe each year and it is the cause of 85,000 deaths annually. 2

Risk factors associated with prostate cancer include family history of the disease, age (predominantly men over 50 years of age) and a diet high in red meat and dairy products. 3

Once the cancer has been diagnosed it is graded and staged to assess aggressiveness of the tumour and how far it has spread, and for evaluating the type of treatment required. Treatment can involve surgery, radiotherapy, hormone treatments and chemotherapy (advanced cases). 3 Prostate cancer diagnosed at an early stage is usually treated by a combination of surgery and radiotherapy; more advanced cases are treated with radiotherapy and hormone therapies such as the anti-androgens. In patients with metastatic disease where the cancer has spread to other parts of the body, a multi-disciplinary approach which could include chemotherapy, is implicated.

###

For further information please contact:
Tonic Life Communications:
Stéphanie Makin: + 44 7769 673 973 or e-mail stephanie.makin@toniclc.com or
Kirsten Mason: + 44 7796 955 353 or e-mail kirsten.mason@toniclc.com

Press room:
Telephone: + 33 (0)1 40 68 27 45/ + 33 (0)1 40 68 27 46
Telefax: + 33 (01) 40 68 27 49/ + 33 (01) 40 68 27 52

For any enquiries after Thursday 3rd November 2005, please contact:
Stéphanie Makin: + 44 (0)20 7798 9905 or e-mail stephanie.makin@toniclc.com or
Kirsten Mason: + 44 (0)20 7798 9911 or e-mail kirsten.mason@toniclc.com

1 Boyle, P et al. The Epidemiology of Prostate Cancer. Urological Clinics of North America. 30(2): 209-217. May 2003
2 Boyle, P. Cancer incidence and mortality in Europe, 2004. International Agency for Research on Cancer. 2004, p.483
3 Cancer reference information - www.cancer.org, www.prostate.com & www.cancer.org.uk

Abstract: Presidential symposium
Radiation dose-response in prostate cancer: results of a multicenter randomized Phase III trial comparing 68 Gy with 78 Gy
Lebesque, JV (1); Peeters, STH (1); van Putten, WLJ (2); Heemsbergen, WD (1); Slot, A (3); Dielwart, MFH (4); Bonfrer, JMG (1); van Leenders, A (2); Koper, PCM (2)
(1) The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands;
(2) Erasmus Medical Centre, Rotterdam, The Netherlands;
(3) Radiotherapeutic Institute Friesland, Leeuwarden, The Netherlands;
(4) Zeeuws Radiotherapeutic Institute, Vlissingen, The Netherlands Purpose:
To determine whether for prostate cancer patients a radiotherapy dose of 78 Gy improves outcome compared with 68 Gy.
Methods and materials:
Between 1997 and 2003, 669 stage T1b-T4N0M0 prostate cancer patients were randomized. Four treatment groups (with specific planning target volumes) were defined based on the probability of seminal vesicle involvement. Stratification was done by hospital, (neo)adjuvant hormonal therapy (HT), age and treatment group. The patients' baseline characteristics were well balanced between both arms (1). Median initial PSA was 13.0 ng/ml (range 0.4-59.0) and 63% had T1-2 tumours. Differentiation grade was good, moderate and poor in 30%, 55% and 15%, respectively. The 3 prognostic risk groups, low, intermediate and high (Symon et al. (2)), included 18%, 27% and 55% of the patients, respectively. HT was prescribed to 143 intermediate and high risk patients. The primary endpoint was freedom from failure (FFF). Failure was defined as clinical failure (clinical relapse or start new HT) or biochemical failure (ASTRO-definition: 3 consecutive PSA rises with backdating). Patients without failure were censored at last contact or at death. Median follow-up time was 51 months.
Results:
FFF at 5 years was significantly better in the 78 Gy-arm compared with the 68 Gy-arm (64% vs. 54%, p=0.025) (Figure). In all treatment groups FFF was higher in the 78 Gy-arm, but only in group II this difference was significant (83% vs. 60%, p=0.006). Of the three risk groups, intermediate risk patients benefited most from dose-escalation (74% vs. 58%, p=0.03). The gain in the high risk group was smaller (52% vs. 44%, p=0.1), and there was no benefit in the low risk group (84% vs. 86%, p=0.7). No significant differences in overall survival (83% vs. 82%) and freedom from clinical failure (76% vs. 76%) were seen between both arms. Multivariate Cox proportional hazards regression showed that the randomization arm was an independent predictor of FFF, along with initial PSA, differentiation grade, T-stage and HT.
Conclusion:
This multicenter randomized trial shows a significantly improved freedom from failure in prostate cancer patients treated to high doses. This benefit was most apparent in intermediate risk patients.

(1) Peeters et al. IJROBP 2005; 61:1019-1034
(2) Symon et al. IJROBP 2003; 57:384-390

Figure: Kaplan-Meier curves for both randomization arms showing freedom from failure

Abstract: Presidential symposium
Adding bicalutamide 150 mg to standard care for localised or locally advanced prostate cancer: results from the largest hormonal therapy trial ever conducted in prostate cancer patients, at over 7 years' follow up

Iversen P,1 McLeod D,2 See W,3 Morris T,4 Armstrong J,4 Wirth M,5 on behalf of the 'Casodex' EPC Trialists' Group
1Dept of Urology, Rigshospitalet, Denmark;
2Walter Reed Army Medical Ctr, Washington, DC, USA;
3Medical College of Wisconsin, Milwaukee, WI, USA;
4AstraZeneca, Macclesfield, UK;
5Dept of Urology, Technical University of Dresden, Germany
Background:
The Early Prostate Cancer (EPC) programme is the largest treatment trial in patients (pts) with localised or locally advanced prostate cancer. The programme is helping to define which pts benefit, and which do not, from early or adjuvant antiandrogen therapy. Third analysis results, at 7.4 years' median follow-up, are presented.
Materials/Methods:
The programme comprises 3 randomised, double-blind, placebo-controlled trials designed for combined analysis. Men (n=8113) with localised (T1-2, N0/Nx) or locally advanced (T3-4, any N; or any T, N+) prostate cancer (all M0) were recruited. Pts received bicalutamide 150 mg (n=4052) or placebo (n=4061) once daily plus standard care (radiotherapy [RT], radical prostatectomy [RP] or watchful waiting [WW]). Primary endpoints were overall survival (OS) and objective progression-free survival (PFS).
Results:
In localised disease, no significant PFS or OS benefit was found with adding bicalutamide to standard care. In locally advanced disease, bicalutamide significantly improved objective PFS irrespective of standard care (WW, HR 0.60; RP, HR 0.75; RT, HR 0.56; p<0.001 for all). Bicalutamide significantly improved OS in pts with locally advanced disease who received RT (HR 0.65; p=0.0276); this was driven by a lower risk of death due to prostate cancer (16.1% vs 24.3%). Bicalutamide produced a trend towards improved OS in pts with locally advanced disease who would otherwise undergo WW (HR 0.81; p=0.057). No OS difference was seen in RP pts.
Conclusions:
The ongoing EPC programme provides clarity on the role of early or adjuvant antiandrogen therapy in pts with prostate cancer. Pts with localised disease do not appear to receive clinical benefit from bicalutamide. Pts with locally advanced disease derive significant clinical benefit from the addition of bicalutamide 150 mg to standard care; in particular, an OS benefit was seen in men who received RT.

Abstract: Presidential symposium
Immunotherapy (APC8015) for androgen independent prostate cancer (AIPC): final progression and survival data from a second Phase 3 trial
C. Higano1, P. Burch2, E. Small3, P. Schellhammer4, R. Lemon5, S. Verjee6, R. Hershberg6
1University of Washington, Seattle, WA, USA
2Mayo Clinic, Rochester, MN, USA
3UCSF Comprehensive Cancer Center, San Francisco, CA, USA
4Eastern Virginia Medical School, Norfolk, VA, USA
5Cancer and Blood Institute, Rancho Mirage, CA, USA
6Dendreon Corporation, Seattle, WA, USA
Background:
APC8015 is an immunotherapy product currently in a pivotal Phase 3 trial for metastatic AIPC. We have reported results from the first of two independent Phase 3 trials, denoted D9901 and D9902A, in asymptomatic metastatic AIPC. D9901 showed a significant survival advantage for APC8015 treated subjects in the intent-to-treat (ITT) group compared with placebo. D9902A is the subject of this abstract wherein final time to objective disease progression (TTP) and survival will be reported.
Methods:
Subjects with asymptomatic metastatic AIPC were randomized (2:1) to APC8015 or placebo, administered in Weeks 0, 2, and 4. Eligible subjects had tumour progression following hormonal therapy, no cancer-related pain or visceral metastases, and positive prostatic acid phosphatase (PAP) staining in at least 25% of tumour cells. Monitoring for the primary endpoint, TTP, was by centrally reviewed serial radiologic imaging. Overall survival is a secondary endpoint and all subjects are being followed for survival for 3 years after randomization. Estimates of TTP and survival will be based on the Kaplan-Meier method (log-rank) with corresponding confidence intervals. A hazard ratio estimating the relative risk of non-progression, placebo:APC8015, will be calculated using a stratified Cox proportional hazards model. In addition, a meta-analysis combining the results from D9901 and D9902A will be presented.
Results:
Ninety-eight subjects were randomized between May 2000 and March 2003. Based on data acquisition and monitoring, these new data will become available mid-2005. This will be the first analysis and presentation of data from this trial.
Conclusions:
In the previous study, D9901, APC8015 resulted in a statistically significant overall survival advantage for subjects with asymptomatic metastatic AIPC, representing the first survival advantage attributed to an immunotherapy product in prostate cancer. D9902A is an independent, Phase 3 study that may provide data to both confirm and strengthen these observations.

Abstract: 807
TROG 96.01: first report of the main endpoints
J.W. Denham, A. Steigler, D.S. Lamb, D. Joseph, S. Turner, J. Matthews, I. Franklin, C. Atkinson, D. Christie, N.A. Spry
University of Newcastle, Radiation Oncology, Waratah, Australia
Background:
To determine whether 3 or 6 months maximal androgen deprivation [MAD] administered prior to and during radiotherapy improves treatment outcomes for patients with locally advanced prostate carcinoma [PC], we conducted a large scale randomised controlled trial.
Material and Methods:
Men with Stage T2bc, T3 and T4 (N0, M0) PC were randomised to radiotherapy alone (66Gy in 2Gy fractions to the prostate and seminal vesicles) [RT], or 3 months MAD (Goserelin 3.6mg im monthly and Flutamide 250mg tds) starting 2 months prior to RT; or 6 months MAD starting 5 months prior to RT.
Results:
Between June, 1996 and February, 2000, 818 men were randomised at 19 Australian and New Zealand centres. 802 were eligible for analysis. In comparison to RT alone 3 months MAD reduced local failure [LF]: HR 0.55 (p=0.001), improved biochemical failure free survival (Houston method) [BFS]: HR 0.71(p=0.003), clinical disease free survival [DFS]: HR 0.66 (p<0.001) and freedom from salvage therapy [FST] HR 0.73 (p=0.024). In addition to producing even greater improvements in LF: HR 0.41(p<0.001), BFS: HR 0.57(p<0.001), DFS: HR 0.55 (p<0.001), FST: HR 0.52 (p<0.001) 6 months MAD also reduced distant failure [DF] HR 0.66 (p=0.04) and produced a significant improvement in cause specific survival: HR 0.58 (p=0.048). In this treatment arm patients with "high risk" cancer also experienced a strong trend towards improved overall survival: HR 0.66 (p=0.066).
Conclusions:
Six months MAD administered prior to and during RT improves all outcomes in patients with locally advanced P.C. Further follow-up is necessary now to estimate the size of survival benefits precisely.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.