A second opportunity to come for anti-angiogenics in prostate cancer?

Better understanding of the biology of advanced prostate cancer has led to unprecedented progress in its therapy over the past few years. The androgen biosynthesis inhibitor abiraterone acetate, the androgen receptor (AR) antagonist enzalutamide, the cytotoxic chemotherapeutics docetaxel and cabazitaxel, the immunotherapeutic sipuleucel-T and the alpha particle-emitting radiopharmaceutical radium-223 have all been shown to extend survival (OS), and in some cases provide symptomatic improvement in phase III clinical trials in patients with metastatic castration resistant prostate cancer (mCRPC) (1-7). While androgen signaling inhibitors and chemotherapy primarily target tumor cells, the effects of radium-223 and particularly sipuleucel-T are likely mediated in part by modulation of the tumor microenvironment, including immune and other stromal cell constituents of the primary tumor and metastatic sites. Thus, targeting components of the microenvironment in prostate cancer can meaningfully affect the rate of cancer progression and survival outcomes.

Tumor growth is often critically dependent on its ability to sustain an adequate blood supply, which, to a different degree depending on cancer type and state, is facilitated by newly developed blood vessels through the process known as tumor angiogenesis. Anti-angiogenic drugs were developed to “starve” tumors by primarily affecting tumor-associated blood vessels. These agents have been mostly designed to inhibit vascular endothelial growth factor (VEGF) signaling, a key mediator of tumor angiogenesis. Several VEGF-targeted drugs (the anti-VEGF monoclonal antibody bevacizumab, the synthetic VEGF trap aflibercept, and the multi-tyrosine kinase inhibitors (VEGFR TKI) sorafenib, sunitinib, pazopanib, axitinib, vandetanib, cabozantinib and regorafenib) have been approved as single agents for solid tumors such as some that respond poorly to conventional chemotherapy (e.g., advanced renal cell, pancreatic neuroendocrine, medullary thyroid and hepatocellular carcinomas), and also in combination with chemotherapy (8). However, the results of controlled clinical trials using anti-VEGF therapies in prostate cancer have so far been disappointing.

A few VEGF inhibitors have been tested in combination with standard first-line docetaxel-based chemotherapy in mCRPC. In phase II clinical trials, bevacizumab and sunitinib showed seemingly modest additional activity when combined with docetaxel (9,10). Yet neither bevacizumab nor aflibercept in combination with docetaxel and prednisone led to improvement in OS as compared with docetaxel and prednisone alone in respectively the CALGB 90401 and VENICE phase III clinical trials, even though bevacizumab resulted in extension of progression-free survival (PFS) and a higher rate of objective responses (ORR) (11,12).

As single agents, sorafenib, sunitinib, and cediranib (a separate VEGFR TKI) showed noticeable but limited activity in phase II studies, both in chemotherapy-naïve patients and after progression to docetaxel (13-16). Interestingly, responses (in pain and scans) were frequently discordant with changes in PSA, which tended to increase during treatment (4 weeks on, 2 weeks off schedule) and drop off it (17). Some of those early trials were designed using PSA response as the primary endpoint, leading to early study closure. Bevacizumab monotherapy, however, did not show clinical activity in mCRPC (18).

Marc Dror Michaelson et al. recently published the results of the international phase III trial of sunitinib plus prednisone versus placebo plus prednisone in patients with progressive mCRPC (SUN 1120) (19). Different to the CALGB and VENICE studies above, sunitinib was used as mainstay treatment without chemotherapy, and following failure of one previous docetaxel-based regimen. Patients (n=873) were randomly assigned 2^:1 to receive the study drug or placebo continuously in combination with oral prednisone. OS, the primary endpoint, did not differ significantly between treatment arms (13.1 vs. 11.8 months respectively for sunitinib and placebo, P=0.168), leading to early termination of the trial after a second interim analysis on the basis of futility. Sunitinib was however comparatively better in secondary endpoints, such as PFS (5.6 vs. 4.1 months, P≤0.001) and ORR in patients with measurable disease (6% vs. 2%, P=0.04). Also to note, the rate of discontinuation of sunitinib before objective disease progression was an important 37%, mostly due to toxicity but also to a high censoring rate from patient termination before disease progression in relation to the early study closure. How the interpretation of PSA raises by the treating oncologists may have influenced their evaluation of response and thus the study results was not formally evaluated.

Together, the data from the sunitinib and the docetaxel and bevacizumab/aflibercept combination phase III trials strongly suggest that there is no general role for limited anti-VEGF therapies in patients with mCRPC, either alone or in combination with docetaxel. The clinical experience suggests that the multi-targeted TKI, particularly sunitinib, are more active in mCRPC than the VEGF ligand blocking drugs as single agent, and that only subsets of individuals seem to obtain benefit. Important challenges therefore remain. What characterizes the disease of the responsive patients? And at what point in the natural history of the disease are anti-angiogenics most beneficial? In the current state of knowledge, the answer to neither question is obvious. In spite of the established relevance of angiogenesis in tumorigenesis, prostate cancer is characterized by a dominance of androgen signaling-related evolutionary and adaptive changes in its castration resistant progression. How each of those changes alters the balance of pro- and anti-angiogenic drivers in the microenvironment and the host, and in the end the relative contribution of tumor angiogenesis through prostate cancer progression remain poorly depicted in patients. Moreover, the consistent tropism of prostate cancer for bone and the inherent difficulty in reliably evaluating disease and treatment-related changes in the osseous environment make this characterization particularly challenging.

Still, it is speculative but probable that a subset of mCRPC patients exist in whom angiogenic mechanisms of progression are important, thus potentially rendering them more responsive to angiogenesis inhibition. For instance, an estimated 10-20% patients treated with sunitinib demonstrate sometimes dramatic bone scan responses, although the translation of these findings into survival outcomes is not available (20). Moreover, the biology of the disease in specific metastatic sites may rely heavily on angiogenesis. This could be the case of lymph nodes, which are the most frequent site of measurable metastasis in mCRPC patients. Both the CALGB 90401 and SUN 1120 studies demonstrated significant improvements in ORR compared to control (11,19).

Regarding timing for application, the limited existing data for bevacizumab and sunitinib in castration sensitive patients (mostly with high-risk prostate cancer) do not suggest that early introduction of VEGF-targeted therapy results in meaningfully better outcomes than in the castration resistant phase, at least in what concerns the primary disease site. However, even complete pathologic responses occur in rare cases (21), suggesting that angiogenesis inhibition can be useful in treating prostate cancer patients.

So what are the possible venues to improve the efficacy of these agents? An obvious one is the definition of predictive molecular and/or genetic markers that enrich for microenvironmental dependence on angiogenesis. Years of research in the field of biomarkers have not yet resulted in the identification of any prospectively validated molecular or cellular surrogate of anti-angiogenic treatment benefit in prostate or any other cancer type. Because of the limited relevance of animal models in prostate cancer and the disease’s inherent heterogeneity, information should originate from characterization of angiogenesis mediators in clinical specimens serially obtained from individual patients. Another comes from the development and application of multi-targeted drugs or combinations that block pathways complementary to VEGF in driving angiogenesis and metastatic progression, or mechanisms of adaptive resistance to angiogenesis inhibition. A very relevant even if a priori unexpected example of this comes from cabozantinib, which inhibits VEGFR and the hepatocyte growth factor (HGF) receptor potently and can result in striking radiologic and pain-relieving responses in mCRPC (22). HGF receptor has been shown to participate in escape from VEGFR inhibition (23) and mediate cross-talk signaling between prostate cancer and host cells in bone metastasis (24). Not surprisingly, cabozantinib is being evaluated as single agent in phase III clinical trials in mCRPC. Combinations of anti-angiogenics with immune and bone metastasis modulatory drugs may also prove useful.

Last is the issue of toxicity, which is quite relevant because mCRPC patients are generally older and more comorbid than those with other tumor types. In CALGB 90401, the number of treatment-related deaths (4% vs. 1.2%) was greater in the experimental bevacizumab arm (11). In SUN 1120, 27% patients abandoned sunitinib therapy because of toxicity before progression, probably affecting the OS results (19). Studies have shown that sudden discontinuation of anti-angiogenic treatment may result in “rebound” production of potentially tumor supportive pro-angiogenic factors. Therefore, it may be useful to sustain or even expand angiogenesis inhibition to other relevant targets beyond disease progression (8). Eight percent of the patients in SUN 1120 had their sunitinib dose escalated, resulting in no apparent effect on clinical outcome. Whether more conservative and thus less toxic doses and schedules than those used in cancers more dependent on angiogenesis would be sufficient to achieve anti-tumor effect in prostate cancer has not been formally tested and warrants consideration.

In spite of so far limited effectiveness and significant toxicity and cost, the available data suggests that angiogenesis inhibition should still be considered a potentially useful strategy for the treatment of prostate cancer. Upcoming clinical trials should be based on rational combinations that include potent but narrow in spectrum (and thus likely less toxic) angiogenesis inhibitors, targeting only specific prostate cancer patient subsets and clinical states. The hope is that next generation profiling technologies soon result in better understanding of the driver genetic and molecular networks in prostate cancer, allowing for optimization of the use not only of angiogenesis inhibitors but of all other treatment options for the welfare of the patients.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Editorial Office, Translational Cancer Research. The article did not undergo external peer review.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.3978/j.issn.2218-676X.2014.04.04). The author has no conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011;364:1995-2005. [PubMed]
2. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013;368:138-48. [PubMed]
3. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012;367:1187-97. [PubMed]
4. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502-12. [PubMed]
5. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 2010;376:1147-54. [PubMed]
6. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010;363:411-22. [PubMed]
7. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013;369:213-23. [PubMed]
8. Ebos JM, Kerbel RS. Antiangiogenic therapy: impact on invasion, disease progression, and metastasis. Nat Rev Clin Oncol 2011;8:210-21. [PubMed]
9. Picus J, Halabi S, Kelly WK, et al. A phase 2 study of estramustine, docetaxel, and bevacizumab in men with castrate-resistant prostate cancer: results from Cancer and Leukemia Group B Study 90006. Cancer 2011;117:526-33. [PubMed]
10. Zurita AJ, George DJ, Shore ND, et al. Sunitinib in combination with docetaxel and prednisone in chemotherapy-naive patients with metastatic, castration-resistant prostate cancer: a phase 1/2 clinical trial. Ann Oncol 2012;23:688-94. [PubMed]
11. Kelly WK, Halabi S, Carducci M, et al. Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401. J Clin Oncol 2012;30:1534-40. [PubMed]
12. Tannock IF, Fizazi K, Ivanov S, et al. Aflibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer (VENICE): a phase 3, double-blind randomised trial. Lancet Oncol 2013;14:760-8. [PubMed]
13. Aragon-Ching JB, Jain L, Gulley JL, et al. Final analysis of a phase II trial using sorafenib for metastatic castration-resistant prostate cancer. BJU Int 2009;103:1636-40. [PubMed]
14. Dror Michaelson M, Regan MM, Oh WK, et al. Phase II study of sunitinib in men with advanced prostate cancer. Ann Oncol 2009;20:913-20. [PubMed]
15. Sonpavde G, Periman PO, Bernold D, et al. Sunitinib malate for metastatic castration-resistant prostate cancer following docetaxel-based chemotherapy. Ann Oncol 2010;21:319-24. [PubMed]
16. Dahut WL, Madan RA, Karakunnel JJ, et al. Phase II clinical trial of cediranib in patients with metastatic castration-resistant prostate cancer. BJU Int 2013;111:1269-80. [PubMed]
17. Zurita AJ, Shore ND, Kozloff MF, et al. Distinct patterns of PSA modulation by single-agent sunitinib before combination with docetaxel and prednisone in patients with metastatic castrate-resistant prostate cancer (CRPCa). J Clin Oncol 2007;25:abstr 5134.
18. Reese DM, Fratesi P, Corry M, et al. A phase II trial of humanized anti-vascular endothelial growth factor antibody for the treatment of androgen-independent prostate cancer. The Prostate Journal 2001;3:65-70.
19. Michaelson MD, Oudard S, Ou YC, et al. Randomized, placebo-controlled, phase III trial of sunitinib plus prednisone versus prednisone alone in progressive, metastatic, castration-resistant prostate cancer. J Clin Oncol 2014;32:76-82. [PubMed]
20. Saylor PJ, Mahmood U, Kunawudhi A, et al. Multitargeted tyrosine kinase inhibition produces discordant changes between 99mTc-MDP bone scans and other disease biomarkers: analysis of a phase II study of sunitinib for metastatic castration-resistant prostate cancer. J Nucl Med 2012;53:1670-5. [PubMed]
21. Zurita AJ, Ward JF, Araujo JC, et al. Neoadjuvant trial of sunitinib malate and androgen ablation (ADT) in patients with localized prostate cancer (PCa) at high risk for recurrence. J Clin Oncol 2011;29:abstr 143.
22. Smith DC, Smith MR, Sweeney C, et al. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J Clin Oncol 2013;31:412-9. [PubMed]
23. Sennino B, Ishiguro-Oonuma T, Wei Y, et al. Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discov 2012;2:270-87. [PubMed]
24. Dai J, Zhang H, Karatsinides A, et al. Cabozantinib inhibits prostate cancer growth and prevents tumor-induced bone lesions. Clin Cancer Res 2014;20:617-30. [PubMed]