Two Paths Forward in Metastatic Castration-Resistant Prostate Cancer

Derleth and Yu have summarized the progress made in treating metastatic castration-resistant prostate cancer (mCRPC).[1] Since the US Food and Drug Administration (FDA) approval of mitoxantrone and docetaxel (Taxotere) in 1999 and 2003, respectively, the agency has approved two other non–androgen receptor (AR)-targeting agents, sipuleucel-T (Provenge) and radium-223 (Xofigo) (although docetaxel may target the AR via the tubulin transport of the AR complex[2]) and two AR-targeting agents, abiraterone (Zytiga) and enzalutamide (Xtandi). In the next several years, the FDA will potentially receive applications to approve orteronel, an AR-targeting agent, as well as tasquinimod and custirsen, both non–AR-targeted agents. Meanwhile, the dual MET/vascular endothelial growth factor (VEGF) inhibitor cabozantinib and the immunotherapeutic agent PROSTVAC are in phase III trials. If the results of these phase III trials are all positive, there could be 11 FDA-approved agents for the treatment of mCRPC within 5 years (Table).

TABLE

Agents for the Treatment of mCRPC That Are FDA-Approved or Soon Likely to Be

Unfortunately, although these agents each extend life, none are curative. Therefore, physicians who investigate and treat mCRPC have two paths they can follow to further improve outcomes:

1. Investigate sequences and combinations to increase duration of disease control.

2. Identify new agents to treat the progressively less AR-driven variants of mCRPC.

If the first path is chosen, the task of the clinical investigator will be daunting, since there are up to 11 factorial combinations. (Over 3.6 million combinations would be possible with just 10 drugs.) Phase I disease-specific combination trials will be difficult to advance to phases II and III. Although progression-free survival endpoints might be achieved, patients would already be receiving most FDA-approved agents in sequence; therefore, overall survival might not be different.

For clinical investigators who choose to follow the second path, the task will be no less daunting. Derleth and Yu reviewed some of the most promising targets, such as inhibitors of phosphatidylinositol 3-kinase (PI3K), poly(ADP-ribose) polymerase (PARP), target of rapamycin complex (TORC), and heat shock protein (HSP). To test these agents, it will be necessary to define the genetic makeup of the tumors and the hosts. This may lead to very small subsets of patients eligible for trials. For example, mCRPC arising in BRCA2-positive men is very rare,[14] yet some PARP inhibitors[15] may be highly potent in that subgroup.

Conducting clinical trials focused on path 2 also raises other challenges. The prospective clinical trial patients:

• Often have immune function and bone marrow compromise after years of glucocorticoids, radiation therapy, and chemotherapy.

• Are likely to be elderly with comorbidities.

• Are likely to have highly proliferative tumors that display significant heterogeneity.

Heitzer et al demonstrated that, after sequencing the DNA of circulating tumor cells (CTCs) from patients with metastatic colon cancer,[16] the CTCs had both “private” mutations (ie, those found only in some CTCs and at a subclonal level in the original tumor) and common mutations (ie, those found in virtually all of the cells). A similar degree of tumor heterogeneity is also seen in mCRPC: Tzelepi et al found that the AR signaling pathway was absent in up to 25% of mCRPC specimens previously treated with chemotherapy.[17]

In conclusion, progress in mCRPC will continue, but at a slower pace due to the complex issues involved.

Financial Disclosure: Dr. Vogelzang serves as a consultant to Bayer/Algeta and Janssen Pharmaceuticals, and as a speaker for Dendreon and Medivation.

References:

REFERENCES

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