Oliver Sartor, MD
Tulane University, New Orleans, LA
Edited from PCRI Insights May, 2009 v 12.2
Editor’s Note: Dr. Sartor provided this updated version of a paper he presented at the
ASCO Genitourinary Cancers Symposium 2009
From several perspectives, bone disease is of particular interest for those treating patients with advanced prostate cancer. First, androgen deprivation therapy (ADT) detrimentally affects bone by causing a loss of bone mineral density and a predisposition to fractures. Second, the metastatic pattern of prostate cancer is remarkably bone tropic with over 90% of patients with metastatic castration-refractory prostate cancer (mCRPC) having radiographic evidence of bony spread.
Though the prevention and treatment of ADT-induced osteopenia/osteoporosis is a rapidly changing and provocative field, this paper will not emphasize that domain. Suffice it to say that bisphosphonates, calcium, and vitamin D are commonly used, and that recently reported trials demonstrate fracture prevention in the context of ADT-treated non-metastatic disease. These are large, prospective, placebo-controlled randomized trials of selective estrogen receptor modulators, such as toremifene, and of antibodiesto a Receptor Activator of Nuclear factor Kappa-B Ligand (RANKL), such as denusomab. Although these agents have yet to be approved by the FDA), it is not unreasonable to expect commercial availability in the next year.
Extensive studies have been conducted, examining the molecular mechanisms of bone tropism, although it is likely that tropism is not a completely accurate term. Instead, the growth of prostate cancer in marrow-containing bone most likely represents bidirectional paracrine interactions between prostate cancer cells and the bone stromal microenvironment that occurred after marrow adhesion. This hypothesis is, in some ways, a variant of the century-old “seed and soil” metastatic hypothesis initially proposed by Paget. Today, however, the tumor cell (the seed) and the bone-stroma (the soil) are thought to have bidirectional effects on each other.
Bone-metastatic disease is incurable despite profound responses to hormonal manipulations. Although this resistance may be attributable to continued androgen receptor signaling, drug resistance has also been postulated to be secondary to the presence of hormonally insensitive cancerous stem cells. Such stem cells are not thought to express PSA or androgen receptor, but their progeny (offspring) express these characteristic PC-associated proteins. Much work has gone into the cancer stem cell concept, but much controversy continues in this area.
All investigators agree that metastatic prostate cancer is a remarkably heterogeneous epithelial tumor from both a morphologic and genetic perspective. This heterogeneity poses a significant issue for molecularly targeted therapies, as it is not expected that all cancerous cells will express pharmacologically relevant targets.
Taken together, therapeutic approaches to mCRPC today may be hypothetically viewed as the challenge of overcoming both epithelial heterogeneity and the hard-to-target cancer stem cells whose growth is peculiarly supported by the bone stromal microenvironment. Such a hypothesis also has therapeutic implications that will be discussed below.
Various therapeutic interventions affecting the bone stromal microenvironment are now under clinical study. (See Table 1.) Bisphosphonates, anti-RANKL antibodies, endothelin-A receptor antagonists, various bone-seeking radiopharmaceuticals, src inhibitors, and antiangiogenic agents all have potential bone stromal-linked mechanisms of action. Stromal-targeted therapies have the theoretic advantage of targeting a relatively homogenous portion of the overall tumor, thereby overcoming some of the problems associated with epithelial cell heterogeneity. Conceivably, these agents may render the “soil” inhospitable, therefore altering the rate of “seed” growth.
The potent bisphosphonate zoledronic acid has been approved by the FDA for the prevention of skeletal-related events (SRE) in mCRPC. However, phase III studies with these agents have yet to demonstrate either a survival advantage in mCRPC, or an alteration in the rate of bone metastases in those with non-metastatic (M0) disease. This agent, like all bisphosphonates, binds to hydroxyapatite and accumulates in bone where it inhibits osteoclast migration and maturation. Interestingly, it was reported at the ASCO GU Cancer Symposium meeting 2009 that the use of an oral bisphosphonate (clodronate) demonstrated a survival advantage in a randomized trial for those with metastatic and hormone-sensitive prostate cancer. No advantage was seen for those with non-metastatic disease.1
Denusomab, an anti-RANKL monoclonal, is currently being studied in phase III trials for androgen-deprivation associated osteopenia/porosis, metastasis and SRE prevention. The metastasis prevention study utilizes patients with non-metastatic (M0) CRPC with a PSA greater than 8 ng/mL, or a PSA doubling time (PSADT) of less than 10 months. These parameters were chosen based on a prior study with zoledronic acid associated with a lower than expected rate of metastatic disease in patients with M0 CRPC (but which used a lower PSA threshold and no PSADT entry criteria).2 Of note, the zoledronic acid study was never completed.
Endothelin A Receptor (ETAR) Antagonism
Two ETAR antagonists are currently in clinical trial. Endothelins have been demonstrated to have a number of effects on both prostate cancer cells as well as osteoblasts, therefore only a component of their putative mechanism of action is targeted to the bone stroma. In the osteoblast, ETAR, antagonism blocks differentiation and promotes apoptosis. A 312-patient randomized ZD4054 phase II trial, reported at the ASCO GU Cancer Symposium 2008 last year,3 demonstrated a survival advantage in patients with mCRPC who were asymptomatic or only mildly symptomatic. (See Figure 1) Currently, larger phase III trials of ZD4054 are being conducted in patients with M0 and patients with mCRPC. Atrasentan trials in patients with M0 and mCRPC failed to pass muster after FDA review, but they have provided valuable insights into natural history. A current phase III trial with atrasentan is underway for patients with mCRPC being treated with docetaxel.
Src Kinase Inhibition
Dasatinib is an inhibitor of various kinases including those associated with the abl, C-kit (CD117), src, and platelet-derived growth factor receptor (PDGFR-alpha and PDGFR-beta) genes. In src knockout (-/-) animals, osteoclasts are fully intact but the cells are functionally impaired and unable to resorb bone. Some data also suggest that src inhibition also stimulates osteoblast differentiation and bone formation. Dasatinib is currently being tested in a phase III mCRPC trial in combination with docetaxel. Given the multiplicity of kinase-inhibiting actions of dasatinib, a mechanistic interpretation of the trial results will be difficult. Regardless, clinical benefit as measured by the usual parameters will drive decisions at the FDA.
Several radiopharmaceuticals bind to various stromal elements selectively expressed in bone. Two beta emitters, samarium-153 EDTMP and strontium-89, are FDA-approved for palliative use. Radium-223, an alpha emitter, is in phase III clinical trials (extra-USA).
Radiopharmaceuticals represent a theoretically attractive approach because they target relatively stable bone stromal elements, yet they have the potential capacity (if dosed appropriately) to inhibit the growth of both heterogeneous metastatic epithelial CRPC cells and the cancerous stem cells that give rise to continued cancer growth despite the administration of conventional hormonal chemotherapy. Further, it may be possible to alter stromal elements via radiation in a manner that inhibits growth-promoting tumor-stromal interactions; older clinical studies indicate that radiated bone may be a less hospitable environment for development of metastatic disease.
Several clinical trials suggesting benefits beyond bone pain palliation have reported using radiopharmaceuticals. A small randomized phase II study by Tu et al4 reported a survival benefit for patients with mCRPC treated with adriamycin plus strontium-89 as compared to adriamycin alone (after excluding those progressing or intolerant of a multi-agent chemotherapy regimen). (See Figure 2.) Morris et al5 has reported reversal of docetaxel resistance in some patients subsequently treated with a combination of docetaxel plus samarium-153 EDTMP. Nilsson et al6 have reported a small randomized phase II trial in mCRPC using radium-223. This trial demonstrated a survival advantage for the isotopic treatment (as compared to placebo) after adjustment for baseline covariates. (See Figure 3.) This trial also demonstrated substantial PSA declines after therapy, unlike monotherapy trials associated with beta emitters.
Antiangiogenic agents, though stromal targeting and potentially relevant to bone metastases treatment, will be considered outside the scope of this presentation. Bevacizumab, sunitinib, thalidomide, and lenalidomide all have potential effects on angiogenesis. Current phase III trials are addressing the use of bevacizumab and sunitinib in mCRPC. Phase III trials with lenalidomide are planned.
Bone stromal targets represent a theoretically attractive option for patients with metastatic castration-refractory prostate cancer. Potentially, these agents have the ability to overcome some of the difficulties associated with tumor cell heterogeneity. Whether these approaches will be relevant to the differentiation, propagation, and growth of tumor-derived stem cells is not clear. While today these various approaches are being examined as single-modality therapies, one might anticipate that in the future, combinations of stromal-targeted agents might be more efficacious. Further basic biology studies may elucidate novel therapeutic targets as this field continues to attract attention from talented investigators.
1 Dearnaley DP, Mason MD, et al. Survival benefit with oral sodium clodronate in metastatic but not localized prostate cancer: Long-term results in MRC PR04& PR05. ASCO Genitourinary Cancers Symposium. 2009;82 (suppl abstr 6).
2. Smith MR, Kabbinavar F, Saad F, et al. Natural history of rising serum prostate-specific antigen in men with castrate non-metastatic prostate cancer. J Clin Oncol. 2005;23:2918-2925
3. Dawson N, Phung D, Morris T, et al. Impact of the specific endothelin A receptor antagonist ZD4054 on overall survival and bone metastasis in patients with hormone-resistant prostate cancer: Results of a phase II trial. ASCO Genitourinary Cancers Symposium. 2008;99 (suppl abstr 7).
4.. Tu SM, Millikan RE, Mengistu B, et al. Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: A randomised phase II trial. Lancet 2001;357:336–341.
5. Morris MJ, Pandit-Taskar N, Stephenson RD, et al. Phase I study of docetaxel (Tax) and 153Sm repetitively administered for castrate metastatic prostate cancer (CMPC). ASCO Annual Meeting Proceedings. 2008;250s (suppl abstr 5001).
6. Nilsson S, Franzén L, Parker C, et al. Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: A randomised, multicentre, placebo-controlled phase II study. Lancet Oncol. 2007;8:587–594.