Phase III trial data suggest potential new treatment strategies for prostate cancer

In the last few years we witnessed the approval of several new agents for metastatic prostate cancer that have resulted in improved overall survival (OS)

This article was extracted from the Congress Daily News

Currently, androgen deprivation therapy (ADT) remains a central part of treatment for patients with high-risk non-metastatic and also metastatic prostate cancer. Despite the generally good response of metastatic disease to this approach, many men will eventually develop castration-resistant prostate cancer (CRPC), for which prognosis is still poor. Data from randomised phase III trials presented at yesterday’s Proffered Paper Session on GU, Prostate, have shown a significant OS benefit in patients with ‘high-volume’ metastatic prostate cancer receiving combined antiandrogen and docetaxel as first-line treatment and have suggested a benefit of adding local radiotherapy to androgen deprivation in newly diagnosed high-risk non-metastatic (M0) prostate cancer.

High-volume prostate cancer is a poor prognostic factor in patients with hormone-naïve metastatic prostate cancer. A retrospective subanalysis from the randomised CHAARTED study in 790 men with first-line metastatic prostate cancer was reported by Dr Christopher Sweeney from the Dana Farber Cancer Institute, Boston, MA, USA. The addition of docetaxel to ADT in patients with high-volume disease improved OS from 32.2 to 49.2 months (p=0.0013). Additionally, combined chemo-hormonal treatment among 518 men resulted in an improvement of: prostate-specific antigen (PSA)<0.2 at 12 months (p=0.0011), time to PSA or clinical progression (p<0.0001) and time to clinical progression (p<0.0001). These results are of substantial clinical relevance and will change practice in patients with high-volume untreated metastatic prostate cancer.

Professor Giuseppe Curigliano from the European Institute of Oncology, Milan, Italy, commented, “The investigators demonstrated that patients with ‘high-volume’, castration-sensitive metabolic disease benefit from upfront docetaxel and it appears to confer a survival benefit that is superior to docetaxel given for metastatic castration-resistant disease. However, there is a need to develop better models to determine who ‘high-’ and ‘low-’ volume disease groups should include to avoid, for example, discrimination between a patient with several small lesions and one with a single large lesion.”

Adding docetaxel to ADT in untreated newly diagnosed, high-volume metastatic prostate cancer improved survival by 17 months.

Dr Charles Ryan from the University of California, San Francisco, USA, reported the final OS results of the randomised COU-AA-302 study in 1088 patients comparing the selective CYP17 inhibitor, abiraterone acetate, plus prednisone over prednisone alone in chemotherapy-naïve metastatic CRPC. Disease progression and survival benefits had previously been reported in a planned interim analysis.1 With a median follow-up of 49.4 months, abiraterone acetate plus prednisone significantly prolonged OS compared with prednisone alone (median OS 34.7 months versus 30.3 months; hazard ratio [HR] 0.80; 95% confidence intervals [CI] 0.69–0.93; p=0.0027).

“In future trials it will be important to select patients responsive versus resistant to abiraterone or other anti-androgen agents” – said Professor Giuseppe Curigliano, commenting on the results.

It has recently been shown that the detection of androgen-receptor splice variant 7 messenger RNA (AR-V7) in circulating tumour cells from men with advanced prostate cancer was associated with resistance to enzalutamide and abiraterone.2 Among men receiving enzalutamide, AR-V7-positive patients had lower PSA response rates than AR-V7-negative patients (0% versus 53%) and shorter PSA progression-free survival (PFS; median 1.4 months versus 6.0 months; p<0.001) and OS (median, 5.5 months versus not reached; p=0.002). Similar findings were made among men receiving abiraterone. These findings require large-scale prospective validation.

Abiraterone acetate plus prednisone prolonged survival compared with prednisone alone in chemotherapy-naïve metastatic CRPC.

This OS benefit was maintained despite the fact that 44% of patients in the control arm subsequently received abiraterone acetate plus prednisone. Tolerability was acceptable, although grade 3–4 adverse events of special interest were more common in the combination arm. These results confirm that the survival benefit of abiraterone acetate seen in patients who previously received chemotherapy is also apparent in chemotherapy-naïve metastatic CRPC.

Dr Kim Chi from the University of British Columbia, Vancouver, Canada, reported that the addition of the targeted agent, custirsen, to docetaxel plus prednisone did not improve survival over docetaxel/prednisone alone. Custirsen is a second generation antisense oligonucleotide that targets clusterin, a pro-survival cellular protein overexpressed in response to cellular stress, such as chemotherapy. Among 1022 randomised patients, there was no OS difference between the treatment arms (median 23.4 months with custirsen versus 22.2 months without; HR 0.93; p=0.21). Furthermore, there were more grade ≥3 toxicities in the custirsen arm and more patients discontinuing due to toxicity (41% compared with 29% in the control arm). The lack of a significant efficacy benefit of custirsen over standard therapy, coupled with the markedly higher incidence of severe adverse events, indicates that custirsen did not add any therapeutic benefit in patients with metastatic CRPC.

The use of radiotherapy in addition to ADT in patients with newly diagnosed non-metastatic (M0) prostate cancer was supported by an analysis of prospectively collected data from the large randomised STAMPEDE trial (ADT versus various treatment combinations), which was presented by Dr Nicholas James from the University of Warwick, Coventry, UK. All 694 patients included in the analysis had been enrolled into the control arm, both before and after the introduction of mandatory radiotherapy in addition to ADT for N0M0 disease. The 2-year OS and failure-free survival (FFS) rates were 95% and 79%, respectively. Although patients with N+ disease had a higher risk of failure than those with N0 disease (HR 1.87), planned radiotherapy improved 2-year FFS for both N0M0 disease (HR 0.33; 95% CI 0.18–0.62) and N+M0 disease (HR 0.45; 95% CI 0.25–0.80) compared with no planned radiotherapy. The results support the findings of previous randomised trials for N0M0 disease3,4 and suggest that patients with N+ non-metastatic disease may also benefit from the addition of planned radiotherapy to ADT. Commenting on the results, Dr Eleni Efstathiou from the MD Anderson Cancer Center, Houston, TX, USA, remarked, “This confirms previously reported trials on locally advanced disease. Importantly, data suggest that lymph node-positive, non-metastatic disease may warrant more aggressive combinatorial strategies incorporating radiotherapy and systemic treatment. Data will need to mature and a confirmatory trial is likely warranted for current practice to be altered. Importantly, safety of such an approach is of the essence, given the involved field and diversity in radiation treatment rendered based on availability. Undoubtedly, the data presented is in line with the biology of the disease.”

Radiotherapy added to ADT improved failure-free survival in patients with newly diagnosed N0M0 and N+M0 prostate cancer.

Results from a late-breaking abstract presented by Dr Jennifer Cullen from Center for Prostate Disease Research, Rockville, MD, USA, in yesterday’s Poster Discussion Session on Genitourinary Tumours, Prostate, demonstrated the utility of the 17-gene Genomic Prostate Score (GPS) in predicting recurrence following radical prostatectomy for localised prostate cancer. Using 402 biopsy specimens from 431 patients, GPS was a significant and independent predictor of the time to biochemical (p<0.001) and metastatic recurrence (p=0.032) and was strongly associated with adverse pathology (p<0.001) and high-grade disease (p<0.001).
In addition to the findings from these trials, the need for a new taxonomy for metastatic prostate cancer to cover the range of molecular subtypes revealed by biopsies was discussed by Dr Mark Rubin from Weill Cornell Medical College, New York, NY, USA, as part of Saturday’s Special Symposium on Precision Medicine in Prostate Cancer. The involvement of different signalling pathways and tumours with alterations in DNA damage repair are among the differences that may help to tailor treatment. Reproducible post-treatment histologic definitions and molecular testing should be included in any future taxonomy.


1. Ryan CJ, et al. N Engl J Med 2013;368:138–48
2. Antonarakis ES, et al. N Engl J Med 2014;371:1028–38
3. Warde P, et al. Lancet 2011;378:2104–11
4. Widmark A, et al. Lancet 2009;373:301–8