Discussion
Meta-analyses suggest that there are no Phase 3 data to demonstrate that the therapeutic options described above — known as second-line hormonal manipulation — will impact overall survival, albeit they may alter PSA kinetics.
Currently, there are no consensus guidelines from the American Urological Association, American Society of Clinical Oncology, National Comprehensive Cancer Network, or European Association of Urology, regarding the ideal scanning frequency for patients at the M0 stage of metastatic castrate resistant prostate cancer (M0CRPC).
A scanning pathway can be extrapolated from data discerned from M0CRPC clinical trials pertaining to the placebo group rates of radiographic progression, specifically from Smith et al. (2005), which looked at a control arm of patients who were being evaluated to prevent the development of bone metastases in the M0CRPC group.1
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In this trial, the control group was randomized to treatment with zoledronic acid. In approximately 200 patients within this group, absolute PSA and PSA doubling time were correlative with potential triggers for clinician guidance for identifying patients at increased likelihood to convert to M1CRPC, specifically when bone scan and/or CAT scans might demonstrate metastases. Smith et al. found that 50% of patients that had a PSA doubling time of less than 10 months and absolute PSA>8ng/dL would subsequently develop bone lesions.
A similar trial was published by Yu et al. (2011) and presented at GU-ASCO in 2010.2 In this trial, a group of M0CRPC patients received oral ZD-4054 in an effort to delay the onset of bone metastasis. Thirty percent (30%) of the patients in this study had a positive bone-mineral density scan or CAT scan at the time of baseline screening.
The take-home messages of the Yu and the Smith studies are that there are M0CRPC patients who urologists/oncologists need to evaluate more aggressively with scans, even though they are asymptomatic, and that there are M0CRPC patients for whom we need to develop a pathway to appropriately scan before they develop symptomatic lesions.
Historically, there have been no approved therapeutic options for the asymptomatic M1CPRC patient. In 2004, docetaxel was approved for patients with MCRPC, whereby the overwhelming majority of recipients have been clinically symptomatic prior to initiating a course of therapy. In April 2010, sipuleucel-T was approved. sipuleucel-T is approved for asymptomatic or minimally symptomatic M1CRPC patients. Minimally symptomatic means that the patients are not receiving opioid analgesics for cancer-related pain.
Zoledronic acid and denosumab are approved anti-resorptive therapeutics indicated to prevent and delay the onset of skeletal related events. Urologists/oncologists should consider appropriate screening of these M0 patients, when appropriate, in order to allow for a full discussion of available and approved therapeutic options.
Recently, the therapeutic options for the asymptomatic and symptomatic CRPC landscape have been burgeoning. The new therapeutic options include docetaxel, sipuleucel-T, cabazitaxel, abiraterone, denosumab, and zoledronic acid.
Also, Phase 3 data have been recently presented for MDV3100 and radium-223, demonstrating a survival benefit for M1CRPC patients after chemotherapy. Although there are new therapies available and others pending, the ideal sequencing regimen is still not certain; furthermore, combination data for these new therapeutics are also lacking. Most oncologists would postulate that there will be some form of multimodality regimen that might lead to further improvement in survival for these patients with advanced MCRPC.
In summary, there are two unmet medical needs that can be derived from this case: 1) optimal treatment for M0CRPC patients is unknown and 2) the optimal diagnostic scanning regimen is also still unknown.
References
- Smith M.R., Kabbinavar F., Saad F., et al. Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer. J Clin Oncol.;23(13):2918-2925.
- Yu E.Y., Massard C., Gross M.E., et al. Once-daily dasatinib: expansion of Phase II study evaluating safety and efficacy of dasatinib in patients with metastatic castration-resistant prostate cancer. Urology. 2011;77(5):1166-1171.
