William Oh, MD
As ongoing research continues to deepen our understanding of prostate cancer biology and resistance mechanisms, our arsenal of therapeutic options for men with castration-resistant prostate cancer (CRPC) has steadily grown. Four general classes of therapeutic agents have emerged so far: cytotoxic chemotherapy (docetaxel [Taxotere] and cabazitaxel [Jevtana]), androgen receptor (AR)-pathway directed therapies (abiraterone [Zytiga], enzalutamide [Xtandi], and apalutamide [Erleada]), bone-targeted therapy (radium-223 [Xofigo]), and active cellular immunotherapy (sipuleucel-T [Provenge]). Each of the drugs in these classes has demonstrated significant clinical benefits in randomized phase III clinical trials in CRPC,1-9
but the duration of response for each remains relatively shortlived and the survival benefits are moderate. There remains a great need for additional treatment options. Here we reexamine the case for platinum therapy.
Past Transplant Experience
Platinum agents have long been studied in metastatic CRPC (mCRPC), but in patient cohorts that are largely molecularly unselected (Table
). Trial experience with single-agent carboplatin,10-13
have generally yielded modest rates of prostatespecific antigen (PSA) decline, improvement in pain, and radiographic response.17
Although platinum doublet combinations with a taxane,18-20
are usually associated with slightly higher rates of PSA decline, they are also associated with increased toxicity. Triplet combination regimens, such as paclitaxel/ estramustine/carboplatin26
or docetaxel/estramustine/ carboplatin27-29
have been found to have significant clinical activity. In one study, docetaxel/estramustine/carboplatin was associated with a ≥50% decline in PSA in 95% of enrolled patients.29
However, these studies were relatively small and these regimens have not been further developed. Of the 3 platinum drugs, cisplatin and oxaliplatin use is often limited by renal impairment and neuropathic toxicity. Carboplatin is generally well tolerated, but has a heavier footprint in terms of myelosuppressive effects.
Satraplatin, a fourth-generation oral platinum analogue, was tested in the randomized phase III SPARC study. A total of 950 men with chemotherapy- refractory mCRPC were enrolled and received either satraplatin plus prednisone or placebo plus prednisone. Although satraplatin was associated with a small, but significant, benefit in progression-free survival (11.1 vs 9.7 weeks; HR, 0.67; 95% CI, 0.57-0.77; P
<.001), improvement in time to pain progression (66.1 vs 22.3 weeks; HR, 0.64; 95% CI, 0.51-0.79; P
<.001), and PSA response (25.4% vs 12.4%; P
<.001), there was no demonstrated difference in median overall survival (OS) compared with placebo (61.3 vs 61.4 weeks; HR, 0.98; 95% CI, 0.84-1.15; P
Although SPARC was ultimately a negative trial and further development of satraplatin stopped, the results again confirm that a subset of patients with mCRPC is responsive to platinum therapy, even as a single agent. Unfortunately, predictive markers to identify the cohort most likely to benefit from platinum therapy could not be developed from SPARC, as correlative and translational studies were not included in the study design.
Currently, outside of small cell carcinoma of the prostate, where platinum therapy is considered standard offering based on limited study findings31-33
and an extrapolation of efficacy data in small cell lung cancer, platinum compounds have not been formally adopted into any professional practice guidelines. This is due to a lack of defined OS benefit in the general nonselected population with prostate cancer.
Table. Platinum Agents Effective in Treating Subtypes of Prostate Cancer
Neuroendocrine Prostate Cancer
It could be argued that adoption of platinum drugs has also been poor due to inadequate characterization of the subtype of patients with CRPC who could benefit from platinum agents. Neuroendocrine prostate cancer (NEPC), a heterogeneous histology34
that most commonly transdifferentiates from preexisting adenocarcinoma as an adaptive response to long-term exposure to androgendeprivation therapy (ADT) and AR blockade,35,36
is classically considered to be responsive to platinumbased therapies. The response rates are as high as 70% in those with poorly differentiated histology.37