Prostate Cancer Outlook for 2017: The Search for Actionable Targets Continues

Julie N. Graff, MD

In recent years, there has been an explosion of information concerning the clinical management of prostate cancer. Although much of this information has advanced the field, it has also sparked many questions. Six therapies have demonstrated improved survival in metastatic castration-resistant prostate cancer (mCRPC), yet there is insufficient data regarding combination and sequencing of these agents, and predicting response or resistance to them.[1-6] Researchers identified the AR-V7 truncating mutation in the androgen receptor as a potential predictor of response to enzalutamide and abiraterone, but there is no available assay for clinical use, and the initial findings remain to be fully validated.[7] Docetaxel chemotherapy plus androgen deprivation therapy (ADT) in newly diagnosed castration-sensitive disease proved more effective than ADT alone and has resulted in patients receiving chemotherapy earlier in the disease course.[8,9] Examination of somatic mutations in mCRPC tumors has identified multiple potentially actionable mutations, yet there are no US Food and Drug Administration (FDA)-approved agents in prostate cancer that target them. Prostate cancer patients, researchers, and clinicians alike await the results of key phase III studies in 2017 that could further impact how prostate cancer is managed.

Androgen Receptor Antagonists

Just as chemotherapy has moved to an earlier position in the disease continuum, second-generation androgen receptor antagonists (apalutamide, darolutamide, and enzalutamide) are vying to do the same. There are currently three phase III studies for patients with nonmetastatic castration-resistant disease using these agents to delay the appearance of metastatic disease. In 2013, the SPARTAN study began enrollment of 1,200 men with nonmetastatic CRPC (sometimes called “M0” disease) to determine if the use of apalutamide (ARN-509) could forestall the development of metastatic disease in this population. Patients at 335 sites in 25 countries were randomly assigned 2:1 to apalutamide 240 mg/day or placebo. There has never been a randomized phase III study in biochemically relapsed prostate cancer that definitively describes whether any intervention in this stage extends overall survival or time to metastatic disease. Furthermore, apalutamide is not yet a standard therapy in any stage of prostate cancer. If this study is positive, it has the potential to be practice-changing by moving treatment with second-generation androgen receptor antagonists to an earlier stage of the disease and potentially securing an FDA approval of apalutamide. If it is negative, we will await the results of the other phase III studies and hold off on the use of these agents until the development of metastatic disease, which is the current practice.

PROSTVAC Vaccine

The results of the PROSPECT trial, a phase III clinical trial of PROSTVAC-VF + granulocyte-macrophage colony-stimulating factor (GM-CSF) vs PROSTVAC-VF without GM-CSF vs placebo in men with asymptomatic or minimally symptomatic mCRPC (ClinicalTrials.gov identifier: NCT01322490), may be announced in 2017. PROSTVAC is an immunologic agent consisting of a heterologous prime-boost regimen with two poxvirus-based vectors to prime the immune system to target prostate-specific antigen (PSA). The trial opened in 2011 and has completed enrollment of approximately 1,300 men. If this study is positive, there will be a seventh treatment option for mCRPC that improves overall survival. The phase II study of this agent resulted in an 8.5% improvement in median overall survival rate (hazard ratio, 0.56) for those who received the vaccine vs the control group.[10] If the phase III study results in this degree of improvement in survival, it could be very attractive to patients with mCRPC and their providers.

AR-V7 Mutation

The AR-V7 truncating mutation leads to a loss of ligand-binding domain in the androgen receptor and was recently associated with lack of response to enzalutamide and the CYP17 inhibitor abiraterone acetate.[7] Antonarakis and colleagues determined the AR-V7 status of men starting on enzalutamide and abiraterone using circulating tumor cells (CTCs) and found that when the AR-V7 mutation was present, there was no PSA response to enzalutamide or abiraterone.[7] There are no completed studies to confirm this finding. Assays of AR-V7 are currently only available for research purposes, but Epic Sciences plans to launch its CTC-based assay for clinical use in 2017. If validated, this assay could be useful after treatment with either enzalutamide or abiraterone to determine whether the patient should receive chemotherapy or the second agent, as the AR-V7 mutation is not associated with resistance to chemotherapy.[11]

DNA Repair Defects

Approximately one-quarter of mCRPC contains DNA repair defects (eg, BRCA mutations), and nearly 12% of patients with advanced prostate cancer also have germline mutations, which could be passed on to their offspring.[12,13] Tumors with DNA repair defects can respond to the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib and potentially to platinum-based DNA damaging agents.[14] There are phase III studies of PARP inhibitors vs standard of care either planned or newly registered (ClinicalTrials.gov identifier: NCT02975934), but these data will not be ready in 2017. These new discoveries are also raising the issue of inheritable cancer risk. Clinicians must also consider how to counsel their patients with advanced prostate cancer about the risk to their children. Until recently, the risk of a germline mutation underlying prostate cancer was felt to be low. Now, clinicians must consider adding genetic counseling to their routine care of prostate cancer. There is not yet a consensus about the optimal approach to this emerging problem.

Immune Checkpoint Inhibitors

Finally, we are beginning to appreciate that immune checkpoint inhibitors could have a role in prostate cancer management. Our group recently described complete PSA responses to the programmed death 1 (PD-1) inhibitor pembrolizumab in 5 (18%) of 28 patients with mCRPC treated with a combination of pembrolizumab and enzalutamide. Results from the first 10 patients were published in 2016.[15] We expect to report results from their tumor biopsies, and are also expanding this study by 30 patients, in 2017. These agents cannot be routinely used in clinical care; in fact, there are now two negative phase III studies of ipilimumab (a cytotoxic T-lymphocyte–associated antigen 4 inhibitor) in prostate cancer patients, and phase III data with PD-1 inhibition are required before it can be recommended.

References:

1. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371:424-33.

2. 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.

3. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-22.

4. 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.

5. 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.

6. 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.

7. Antonarakis ES, Lu C, Wang H, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014;371:1028-38.

8. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373:737-46.

9. James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016;387:1163-77.

10. Kantoff PW, Schuetz TJ, Blumenstein BA, et al. Overall survival analysis of a phase II randomized controlled trial of a poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol. 2010;28:1099-105.

11. Antonarakis ES, Lu C, Luber B, et al. Androgen receptor splice variant 7 and efficacy of taxane chemotherapy in patients with metastatic castration-resistant prostate cancer. JAMA Oncol. 2015;1:582-91.

12. Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161:1215-28.

13. Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375:443-53.

14. Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373:1697-708.

15. Graff JN, Alumkal JJ, Drake CG, et al. Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. Oncotarget. 2016 Jul 12. [Epub ahead of print]