HOLLYWOOD, Florida — For men with castration-resistant prostate cancer (CRPC), treatment options are still far from ideal; however, a handful of new and emerging therapies might help stave off disease progression and improve overall survival, according to those involved in updating National Comprehensive Cancer Network (NCCN) prostate cancer guidelines.
"The time period is often measured in decades from the time a man is diagnosed, and the good news is that many men are still living longer than their physicians," said Andrew J. Armstrong, MD, ScM, from the Duke Cancer Institute in Durham, North Carolina.
The most significant changes reflected in the NCCN guidelines are in recommendations for systemic therapies in men with metastatic CRPC, Dr Armstrong said here at the here at the NCCN 20th Annual Conference.
"This term 'castration-resistant disease' really evolved over the past several decades — from 'endocrine refractory' to 'androgen independent' to 'hormone-refractory disease' — based on new information around disease biology. This biology has indicated that the androgen receptor remains a key target in this disease," he explained.
In a 2010 study, Dr Armstrong and his colleagues found that four major prognostic markers can be used to stratify men with CRPC into risk categories predictive of overall survival: pain requiring opiates for control, visceral metastases, the presence of new bone lesions on bone scan, and anemia (Eur J Cancer. 2010;46:517-525).
Table. Association Between Risk Factors and Overall Survival
| Number of Risk Factors | Risk Category | Overall Survival, Months |
| 0 or 1 | good | 25.7 |
| 2 | intermediate | 18.7 |
| 3 or 4 | poor | 12.8 |
The NCCN guidelines note that as disease progresses, men with metastatic prostate cancer could benefit from a sequence of therapies.
| Options for Initial Therapies in the Sequence |
| The established anti-androgenic agents bicalutamide, flutamide, and nilutamide, and the newer agent enzalutamide (Xtandi, Astellas Pharma) |
| Androgen synthesis inhibitors such as ketoconazole and abiraterone acetate (Zytiga, Janssen Biotech) |
| Immunotherapy with sipuleucel-T (Provenge, Dendreon Corp.) |
| Chemotherapy with docetaxel (Taxotere and generics), cabazitaxel (Jevtana, sanofi-aventis), or mitoxantrone |
| Radiopharmaceutical therapy with radium-223 |
| Investigational options |
| Supportive care with bone support (bisphosphonates and denosumab [Xgeva, Amgen]), as well as exercise, sunlight, vitamin D and calcium supplementation, palliative radiation, and/or radiopharmaceuticals |
Recent changes to the NCCN guidelines include a recognition that docetaxel can be repurposed in metastatic CRPC, as supported by the CHAARTED trial. It was demonstrated in that trial that median overall survival was 13.6 months longer with the combination of androgen-deprivation therapy (ADT) plus docetaxel than with ADT alone, and in men with high-volume metastatic disease, median overall survival was 17.0 months longer.
The guidelines also include recommendations about sipuleucel-T, supported by the IMPACT trial, in which median overall survival was 4.1 months longer with sipuleucel-T than with placebo, translating into a 22% reduction in the risk for death.
Data from the PREVAIL trial supported new recommendations on the use of enzalutamide. In that trial, enzalutamide was better than placebo at extending progression-free survival and reducing the risk for death. And in subsets of men with metastases to visceral organs, bone, or lymph nodes — all of whom have generally worse outcomes — enzalutamide prolonged progression-free survival.
New recommendations on the use of abiraterone acetate plus prednisone are based on results from the phase 3 COU-AA-302 registration trial, in which the abiraterone combination was associated with a doubling of progression-free survival over prednisone and placebo (16.5 vs 8.3 months). In addition, median overall survival was significantly better in the abiraterone group than in the placebo group (not reached vs 27.2 months; hazard ratio, 0.57; P = .01).
For men diagnosed with metastatic CRPC, options recommended in the guidelines for first-line therapy are enzalutamide, abiraterone plus prednisone, and docetaxel plus prednisone.
On the Horizon
Ongoing clinical trials that have the potential to change clinical practice are looking at new strategies. One such trial is comparing the combination of palliative radiotherapy with the CTLA-4 blocker ipilimumab (Yervoy, Bristol-Myers Squibb) and the novel immunomodulator tasquinimod with placebo prior to docetaxel chemotherapy. Another trial is evaluating novel hormonal therapies, and still another is conducting a head-to-head comparison of cabazitaxel and docetaxel in the frontline treatment of men with CRPC.
"In these new studies, prednisone is omitted, so can we skip prednisone everywhere we use docetaxel?" asked Wojciech Dolata, MD, from the Allan Blair Cancer Centre in Regina, Saskatchewan, Canada, who was not involved in guidelines development.
In fact, he wondered whether the category 1 recommendation to use docetaxel with prednisone was included in the guidelines because of previous studies in which the combination was compared with mitoxantrone and prednisone.
"Prednisone was one of the first drugs studied in prostate cancer, and it never has had a survival benefit alone," Dr Armstrong reported. "Because it was available back in the 1940s and 1950s, it became the backbone or standard of care with which mitoxantrone was compared, and mitoxantrone required prednisone because it was thought to be unethical not to give prednisone."
"The strict interpretation of all the evidence has been that prednisone is used in the CRPC setting because we don't have any clinical trials without prednisone," he explained.
Dr Dolata told Medscape Medical News that although it is too early for most of the information he heard to influence day-to-day clinical practice, he is interested in the study comparing docetaxel with cabazitaxel in the frontline setting for men with CRPC, and hopes to include his patients in that or a similar trial.
Dr Armstrong reports financial relationships, including consulting fees, honoraria, research support, and speaker's bureau membership, with several pharmaceutical companies. Dr Dolata has disclosed no relevant financial relationships.
National Comprehensive Cancer Network (NCCN) 20th Annual Conference. Presented March 12, 2015
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