Visceral Metastases in Prostate Cancer: An Underestimated and Understudied Subgroup

With the emergence of many new treatment options for metastatic castration-resistant prostate cancer (mCRPC) in the past several years, the medical management of late-stage prostate cancer (PC) has become increasingly complex. It is no longer simply a question of the timing of chemotherapy in this setting, but rather of the sequencing of highly active hormonal agents, autologous cellular immunotherapy, and alpha-emitting radiopharmaceuticals, in addition to multiple cytotoxic chemotherapy options. In the excellent review by Dr. Drake in this issue of ONCOLOGY,[1] the clinical situation of visceral metastatic disease in PC is highlighted. With more and better therapeutic tools at our disposal, it is time to rethink our approach to patients with visceral disease from PC.

The real frequency of visceral involvement in metastatic PC is difficult to define, and Dr. Drake notes that non-lymphoid, soft-tissue metastatic disease is seen in 20% of patients enrolled in first-line clinical trials for mCRPC. Estimates from patients enrolled in clinical trials might not reflect what happens in the real-world setting. Selection for clinical trials is based on strict inclusion and exclusion criteria in order to enroll a defined and homogenous patient population. One recent single-institution comparison found that patients with mCRPC receiving docetaxel on clinical trials tended to be younger, have better baseline performance status, experience fewer and less severe adverse events, and have increased survival compared with patients with mCRPC treated off-protocol.[2] A recent analysis of US medical claims data suggested that the frequency of visceral disease may be much greater than was previously estimated. In this clinical cohort, 38% of patients with newly diagnosed metastatic PC had visceral lesions.[3] Therefore, the visceral metastatic pattern in PC in clinical trial populations likely underestimates the frequency with which this pattern occurrs in non-trial settings, where it appears to represent a substantial number of mCRPC patients.

As noted by Dr. Drake, it is widely accepted that visceral disease is a marker for poor prognosis in PC. Many clinicians have treated this subgroup of patients with early exposure to chemotherapy.[4] It is clear that in other cancers, such as breast, colon, and lung cancer, advances have been made and molecular subtypes have been established that dictate treatment decisions. For example, genomic profiling has established the luminal, human epidermal growth factor receptor 2 (HER2)-enriched, and triple-negative subtypes in breast cancer. In metastatic colorectal cancer, biologic therapy is selected according to the Kirsten rat sarcoma viral oncogene homolog (KRAS) status. Anaplastic lymphoma kinase (ALK) fusion oncogene–positive non–small-cell lung cancer is recognized as a distinct subtype and treated with crizotinib. In contrast, for mCRPC we lack a molecularly detailed classification. Differences between the molecular and immunologic profiles of PC visceral metastases and those of bone lesions have been preliminarily explored but remain poorly defined.[5] Initial data have suggested differences in the expression of survival proteins, epithelial to mesenchymal transition markers, and osteomimetic pathways.[6] As work progresses in this field of molecular profiling, we currently may use clinical factors such as visceral involvement to begin to better select therapy for mCRPC.

The optimal treatment of individuals with mCRPC with visceral metastasis is not well defined. Historically, oncologists have favored treating these patients aggressively with chemotherapy, even platinum-based regimens. With recent work in the field, it is now emerging that despite the clear negative prognostic impact of visceral disease, several agents provide benefit in those with mCRPC and visceral involvement.[7] Retrospective subgroup analyses of docetaxel trials in the mCRPC setting have confirmed the efficacy of this agent.[8] Additionally, we have learned that highly active hormonal agents, such as abiraterone and enzalutamide, provide benefit to patients in this cohort.[9,10] The efficacy of immunotherapy in this setting, however, is largely unknown, given that patients with visceral involvement were excluded from several pivotal immunotherapy clinical trials in mCRPC. To compound the problem, those with visceral metastatic disease were included in the phase III trial of ipilimumab in mCRPC, but it is likely that the apparent lack of efficacy in that subset will bias the design of future studies towards not including this poor-prognosis subgroup.[11] As pointed out by Dr. Drake, in the visceral disease scenario several cytokines mediate systemic immunosuppression. Immune treatments in this setting may be unable to counteract the established cancer-related immune system dysregulation. Timing of immune therapies may play a key role for treatment efficacy. Therefore, it is possible that clinical trials focused on earlier use of immunotherapy in a population largely devoid of visceral metastasis may still show benefit.

In addition to the microenvironment or “evil humors” hypothesis suggested by Dr. Drake, the pattern of metastasis may be due in part to selective pressure. Visceral disease might alert the clinician to the development of a distinct tumor phenotype. Often, physicians treating mCPRC see individuals progressing to aggressive disease after hormonal treatments. Frequently this transition includes the involvement of visceral sites and a tumor burden out of proportion to their prostate-specific antigen level. Underlying this disease course, there are pathologic changes from the classic prostate adenocarcinoma to a neuroendocrine or anaplastic PC, a phenotype with little or no dependence on the androgen receptor pathway.[12] This entity has been reported to respond to platinum therapy, and this fact suggests a separate tumor biology.[13]

In summary, visceral metastatic disease encompasses a substantial portion of men with mCRPC. This is clearly a poor-prognosis group and appears to be underrepresented in clinical trials. With a multitude of new and emerging treatments, a special effort to design clinical trials for those with visceral disease should be undertaken. While evidence points to benefit from highly active hormonal agents (abiraterone and enzalutamide) in this setting, the usefulness of immunotherapy is much less clear. The sense of nihilism that has sometimes accompanied the clinical approach to these patients should be shed, and a renewed effort to improve the care of those with this potentially underestimated and certainly understudied entity should be undertaken.

Financial Disclosure:Dr. Flaig has received honoraria from Bavarian Nordic and GTx, and he has received research support from Cougar Biotechnology, Dendreon, Exelixis, Janssen, Medivation, Roche/Genentech, and Sanofi. Dr. Bourlon has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

1. Drake CG. Visceral metastases and prostate cancer treatment: ‘die hard,’ ‘tough neighborhoods,’ or ‘evil humors’? Oncology (Williston Park). 2014;28:974-80.

2. Templeton AJ, Vera-Badillo FE, Wang L, et al. Translating clinical trials to clinical practice: outcomes of men with metastatic castration resistant prostate cancer treated with docetaxel and prednisone in and out of clinical trials. Ann Oncol. 2013; 24:2972-7.

3. Flaig TW, Mehra M, Potluri R, et al. Real world data analysis of incident metastatic (M1) prostate cancer (PC) patients (pts): US claims database analysis. Ann Oncol. 2014;25(suppl 4):iv275:abstract 794P.

4. Sella A, Konichezky M, Flex D, et al: Low PSA metastatic androgen-independent prostate cancer. Eur Urol. 2000;38:250-4.

5. Ruppender NS, Morrissey C, Lange PH, Vessella RL. Dormancy in solid tumors: implications for prostate cancer. Cancer Metastasis Rev. 2013;32:501-9.

6. Hiader M, Coleman I, Zhang X, et al. Does tumor microenvironment affect the response of castration resistant prostate cancer to therapy in bone vs visceral metastases? Proc Am Urol Assoc Annu Meet. 2014;4(suppl):abstr MP49-15. Available from: https://www.auanet.org/university/abstract_detail.cfm?id=MP49-15&meetingID=14ORL. Accessed November 4, 2014.

7. Halabi S, Lin CY, Kelly WK, et al. Updated prognostic model for predicting overall survival in first-line chemotherapy for patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2014;32:671-7.

8. Berthold DR, Pond GR, Soban F, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol. 2008;26:242-5.

9. Goodman OB, Jr., Flaig TW, Molina A, et al. Exploratory analysis of the visceral disease subgroup in a phase III study of abiraterone acetate in metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis. 2014;17:34-9.

10. Loriot Y, Fizazi K, De Bono JS, et al. Outcomes in patients with liver or lung metastatic castration-resistant prostate cancer (mCRPC) treated with the androgen receptor inhibitor enzalutamide: results from the phase III AFFIRM trial. J Clin Oncol. 2013;31(suppl):abstr 5065.

11. Drake CG, Kwon ED, Fizazi K, et al. Results of subset analyses on overall survival (OS) from study CA184-043: Ipilimumab (Ipi) versus placebo (Pbo) in post-docetaxel metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2014:32(suppl 4):abstr 2.

12. Aparicio A, Logothetis CJ, Maity SN. Understanding the lethal variant of prostate cancer: power of examining extremes. Cancer Discov. 2011;1:466-8.

13. Wang HT, Yao YH, Li BG, et al. Neuroendocrine prostate cancer (NEPC) progressing from conventional prostatic adenocarcinoma: factors associated with time to development of NEPC and survival from NEPC diagnosis-a systematic review and pooled analysis. J Clin Oncol. 2014;32:3383-90.