Building on Last Year’s Advances

Tomasz M. Beer, MD, FACP

Inside ASCO 2015: Prostate Cancer

The 2015 ASCO Annual Meeting delivered new practice-changing results in the area of prostate cancer. Here are the meeting’s main themes:

Chemotherapy expands-but how far?

The results with perhaps the greatest impact were those reported by the STAMPEDE investigators.[1] STAMPEDE is a randomized trial that has been recruiting men starting long-term hormone therapy for high-risk, locally advanced prostate cancer, relapsing disease after primary therapy, or metastatic prostate cancer. Multiple arms of the study are testing the addition of various agents to standard hormonal therapy. The results of adding docetaxel, zoledronic acid, or both were reported at ASCO. Docetaxel was given at 75mg/m² for 6 every-3-weeks cycles, along with prednisolone, 10 mg daily. A total of 2,962 patients were randomized to the four arms. The addition of docetaxel, regardless of zoledronic acid use, significantly improved overall survival (OS), with a hazard ratio (HR) of 0.76 overall and 0.73 for patients with metastatic disease. The results in nonmetastatic disease were less clear, as there were fewer patients in this cohort. These findings confirm the results of the CHAARTED trial that was presented at the 2014 ASCO Annual Meeting and establish a clear standard of care: chemotherapy should be added to hormonal therapy in the initial management of fit patients who present with advanced metastatic prostate cancer.

In Radiation Therapy Oncology Group study 0521, the early use of chemotherapy was also evaluated, along with radiation and hormonal therapy, in high-risk localized disease.[2] Six hundred twelve patients with localized prostate cancer and features consistent with a high risk of relapse were treated with radiation therapy and 2 years of hormonal therapy with or without 6 cycles of docetaxel. The addition of chemotherapy resulted in an improvement in the 4-year OS (HR, 0.68), as well as an improvement in 5-year disease-free survival (HR, 0.76). Although the number of deaths was still very low, the trial provides evidence that the inclusion of docetaxel in the initial regimen for high-risk localized prostate cancer does appear to benefit patients. It is the first evidence of an adjuvant chemotherapy benefit in prostate cancer-and is consistent with the results of CHAARTED and STAMPEDE, which show the value of chemotherapy in the initial management of metastatic disease. However, these results are early, and additional follow-up, with more robust OS data, is needed before we can recommend routine use of chemotherapy in the adjuvant setting.

Hormonal therapy: an old dog…still learning new tricks

Treatment for PSA-only (biochemical) relapse after prostatectomy often includes radiation therapy. Unlike in newly diagnosed disease, where the concurrent use of hormonal therapy is well established, combined-modality therapy has not been extensively studied in this setting. The GETUG-AFU 16 trial randomized nearly 750 patients to salvage radiation with or without 6 months of hormonal therapy.[3] Progression-free survival (PFS) was significantly improved at 5 years with the addition of hormonal therapy, while OS remained high in both groups. This result is quite encouraging for the application of combination therapy in the salvage setting, but it does not yet establish a firm standard of care. Improvements in PFS would be expected with an additional treatment. Longer-term follow-up, which would provide more revealing OS data, will be of significant interest.

The timing of initial hormonal therapy has long been a matter of debate, and in the setting of a rising PSA level, this issue has been particularly vexing. Trans Tasman Radiation Oncology Group 03.06 and Victorian Cooperative Oncology Group PR 01-03 investigators randomly assigned 293 men with a biochemical relapse or localized disease not suitable for therapy with curative intent to immediate vs delayed hormonal therapy.[4] The aim of the study was to have the treatment delay be at least 2 years. In the delayed-therapy arm, 34% of patients started hormonal therapy within 2 years, while 49% started treatment after more than 4 years of observation or had not yet commenced therapy. OS was significantly higher in the immediate-therapy arm, with 6-year survival rates of 81% and 65%, respectively. The planned accrual was 750 patients, and the patient groups were heterogeneous, as were the approaches to hormonal therapy. Thus, the results warrant cautious interpretation. Still, they do suggest a possible value to earlier use of hormonal therapy. Larger, more definitive studies are needed.

The toxicity of hormonal therapy over the long term has been a vexing concern. One strategy that was designed in the hope of reducing the morbidity of hormonal therapy is its intermittent application.[5] Southwest Oncology Group (SWOG) investigators evaluated a subset of patients from S9346, a randomized SWOG trial of intermittent vs continuous androgen deprivation therapy in patients with metastatic prostate cancer that was designed to evaluate long-term morbidity. To capture events that might not have been captured in the study database, the investigators linked trial data to corresponding Medicare claims-an unusual approach. The analyzed subset represents those patients who had continuous Medicare parts A & B coverage for at least a year and no health maintenance organization participation. Surprisingly, the authors found that older men assigned to intermittent therapy had a slightly increased incidence of ischemic and thrombotic events and no reduction in bone-related, endocrine, or cognitive events. A possible explanation for the unexpected findings is that the cycles of hormonal changes produce increased risks. These results should be viewed as preliminary, however, as the methodology used has significant limitations; still, the overall study results called for continuous therapy as the standard of care for men with metastatic prostate cancer-based on efficacy. These safety analyses certainly do not provide a counter argument.

Hormonal therapy is routinely combined with radiation for the treatment of high-risk and most intermediate-risk patients. But in intermediate-risk patients, the combination is not as well studied and questions about the need for hormonal therapy-particularly with improving radiation delivery-have been raised. A randomized trial that involved 600 participants showed that biochemical and disease-free survival with 6 months of hormonal therapy plus radiation were superior even to results with dose-escalated radiation, providing support for the widely practiced approach of combining these two treatment modalities.[6]

At the 2014 ASCO Annual Meeting, the initial results of PREVAIL, the phase III trial that examined enzalutamide vs placebo in chemotherapy-naive patients with metastatic castration-resistant prostate cancer, were presented. The trial was stopped early due to favorable results, and enzalutamide gained approval for use in the prechemotherapy setting. However, because the trial was stopped at the interim analysis, the results were early and OS estimates were unstable. More mature results were presented at this year’s meeting. The median OS in a mature analysis (which included patients who crossed over to enzalutamide) was improved by 4 months compared with placebo (35 vs 31 months), and median PFS was 20 months with enzalutamide, compared with 5 months with placebo.[7]

Advances in our understanding of prostate cancer biology-with potential clinical utility

Two Stand Up to Cancer/Prostate Cancer Foundation Dream Teams are working to radically improve our understanding of the biology of advanced prostate cancer and apply this knowledge to the development of methods for selecting patients with advanced prostate cancer for precision treatment. The West Coast Dream Team reported that a distinct histology that features neuroendocrine differentiation but retains some features of adenocarcinoma is common, is associated with a poor prognosis, and has a distinct molecular profile that may facilitate the use of dedicated treatments.[8] This new subtype was named “intermediate atypical carcinoma.” A companion analysis reported that androgen receptor amplification was common in tumors from patients not treated with abiraterone or enzalutamide, and that it was also present, although less common, in abiraterone-pretreated tumors.[9]

Financial Disclosure: Dr. Beer receives research funding from Astellas, Bristol-Myers Squibb, Dendreon, Janssen, Medivation, OncoGenex, and Sotio. He serves as a consultant to Astellas, Bayer, and Sotio.

References:

1. James ND, Sydes MR, Mason MD, et al. Docetaxel and/or zoledronic acid for hormone-naïve prostate cancer: first overall survival results from STAMPEDE (NCT00268476). Presented at the American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2015; Chicago. Abstr 5001.

2. Sandler HM, Hu C, Rosenthal SA, et al. A phase III protocol of androgen suppression (AS) and 3DCRT/IMRT versus AS and 3DCRT/IMRT followed by chemotherapy (CT) with docetaxel and prednisone for localized, high-risk prostate cancer (RTOG 0521). Presented at the American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2015; Chicago. Abstr LBA5002.

3. Carrie C, Hasbini A, De Laroche G, et al. Interest of short hormonotherapy (HT) associated with radiotherapy (RT) as salvage treatment for biological relapse (BR) after radical prostatectomy (RP): results of the GETUG-AFU 16 phase III randomized trial-NCT00423475. Presented at the American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2015; Chicago. Abstr 5006.

4. Duchesne GM, Bassett J, D’Este C, et al. TROG 03.06 and VCOG PR 01-03: the “timing of androgen deprivation therapy in prostate cancer patients with a rising PSA (TOAD)” collaborative randomised phase III trial. Presented at the American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2015; Chicago. Abstr 5007.

5. Hershman DL, Unger JM, Wright JD, et al. Long-term consequences of intermittent and continuous androgen deprivation in older patients with metastatic prostate cancer. Presented at the American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2015; Chicago. Abstr 5008.

6. Nabid A, Carrier N, Vigneault E, et al. A phase III trial of short-term androgen deprivation therapy in intermediate-risk prostate cancer treated with radiotherapy. Presented at the American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2015; Chicago. Abstr 5019.

7. Beer TM, Armstrong AJ, Sternberg CN, et al. Enzalutamide (ENZA) in men with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC): final analysis of the phase 3 PREVAIL study. Presented at the American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2015; Chicago. Abstr 5036.

8. Small EJ, Huang J, Youngren J, et al. Characterization of neuroendocrine prostate cancer (NEPC) in patients with metastatic castration resistant prostate cancer (mCRPC) resistant to abiraterone (Abi) or enzalutamide (Enz): preliminary results from the SU2C/PCF/AACR West Coast Prostate Cancer Dream Team (WCDT). Presented at the American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2015; Chicago. Abstr 5003.

9. Aggarwal RR, Thomas G, Youngren J, et al. Androgen receptor (AR) amplification in patients (pts) with metastatic castration resistant prostate cancer (mCRPC) resistant to abiraterone (Abi) and enzalutamide (Enz): preliminary results from the SU2C/PCF/AACR West Coast Prostate Cancer Dream Team (WCDT). Presented at the American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2015; Chicago. Abstr 5068.