With increasing evidence that prostate-specific antigen (PSA) is not an ideal marker for prostate cancer, research efforts are focused on identifying efficient biomarkers for disease diagnosis as well as response to treatment. Additionally, this form of cancer is known to rapidly adapt and develop resistance to androgen-deprivation therapy (ADT), the most commonly used hormone therapy for prostate cancer.
To shed some light on the current status of prostate cancer diagnosis, and to gain insight into the clinical pathways followed to treat the resistant form of the disease, The American Journal of Managed Care invited comment from Ira M. Klein, MD, MBA, FACP, national medical director, Clinical Thought Leadership, Office of the Chief Medical Officer, Aetna Inc; and Christopher Sweeney, MBBS, associate professor, Department of Medicine, Harvard Medical School, and medical oncologist, Dana-Farber Cancer Institute. Peter Salgo, MD, professor of medicine and anesthesiology at Columbia University and associate director of surgical intensive care at NewYork-Presbyterian Hospital, interviewed Klein, while Silas Inman, director, editorial and multimedia, OncLive, interviewed Sweeney.
The discussion started with the experts being asked to comment on new and emerging diagnostic and prognostic markers in prostate cancer, to which both Sweeney and Klein responded by saying that currently there is nothing beyond PSA, although this antigen “has a terrible track record in terms of its predictive value, and we have a lot of people getting unnecessary prostate biopsies,” according to Klein. He went on to add that for individuals with high PSA levels whose biopsies come back positive, traditional methods of Gleason score and tumor morphology follow. Klein emphasized that the patient’s age is an important consideration when choosing the treatment pathway because a balance between life expectancy and aggressiveness of treatment is vital. With respect to epigenetic markers to understand disease progression, Klein thinks we are in the very early stages, at least when it comes to prostate cancer; current epigenetic data on prostate cancer are not sufficient to determine which patients with metastatic disease will progress, which might be due to tumor heterogeneity.
Salgo asked Klein whether patients who might develop ADT resistance can be identified, and whether tumor heterogeneity might be the driving force. According to Klein, it’s a tough predicament because we currently cannot identify hormone-resistant patients prior to initiating hormone therapy. While tumor heterogeneity is known to exist in prostate cancer, it’s not well defined. “Some of the trials that are ongoing are evaluating this,” Klein added, combining androgen blockade with traditional chemotherapy and comparing the response with androgen blockade alone. According to Sweeney, while the time frame for progression to resistance on luteinizing hormone—releasing hormone (LHRH) agonists is variable, very few patients progress within the first 6 months. Sweeney affirmed, however, that it is possible to identify and segregate patients based on the rate at which their disease will progress—a finding from the “ChemoHormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease” (CHAARTED) study. “One feature that we presented in the CHAARTED studies, which has also been seen in other studies, is that patients who have a higher volume of disease at presentation have a shorter time to progression,” said Sweeney. Thus, the extent of disease that the patient presents with prior to staring therapy, and the impact on PSA after initiating therapy, determine the time to progression, he said. Tumor heterogeneity could be a risk factor for differential responses to therapy—an area of research actively being pursued. One such finding is the expression of a splice variant of the androgen receptor (AR), a truncated form which functions independent of androgen and drives cancer progression independent of the blocking testosterone or the wildtype AR, he said. Sweeney highlighted a study in The New England Journal of Medicine that found patients expressing this truncated AR resistant to both abiraterone and enzalutamide,1 and he believes this is a promising biomarker that could help distinguish between good and poor responders.
Inman asked about the use of combination therapies in prostate cancer and where the field currently stands. Sweeney, who has played a major role in the CHAARTED study since its inception in 2004, responded that the study has reported promising results from combining hormones with chemotherapy early in treatment, adding that ongoing trials are evaluating the introduction of enzalutamide or abiraterone early in treatment. Another trial, said Sweeney, is studying androgen deprivation in combination with enzalutamide and docetaxel at initiation, to target the less resistant cells, based on the hypothesis that “It would delay progression further and improve survival even further.”
Inman asked Sweeney to provide details on CHAARTED, a randomized phase 3 study comparing androgen deprivation with or without docetaxel, followed by a lag period, and then hormone therapy alone. The results were quite encouraging among patients with a high-volume disease (liver or lung metastases and ≥4 bony metastases), Sweeney said, with highvolume patients showing an increase in median survival from 32 months to 49 months. Early chemotherapy resulted in a 40% reduction in the risk of death, suggesting that high-volume patients treated with the combination lived longer, he said. With the low-volume patients, Sweeney continued, 70% were still on the study without disease progression at 4 years, independent of chemotherapy, indicating that the response to chemotherapy in this population would need a longer followup. He agreed that in older patients with a low-volume disease, aggressive chemotherapy may not be an ideal choice.
The discussion then moved to sequencing therapies in prostate cancer; current National Comprehensive Cancer Center (NCCN) guidelines have no recommendations for the sequencing of antiandrogens (enzalutamide) with androgen synthesis inhibitors (abiraterone), pre- or post chemotherapy. Klein said that Aetna works with consultants who have pointed to the lack of information on some of these agents for recommending a sequence of drugs to use in treatment regimens. However, he alluded to the fact that abiraterone has been approved and has been in use for some time now, while enzalutamide is a fairly new drug but should be accessible in the near future. Prospective trials evaluating the combination of abiraterone and enzalutamide in advanced prostate cancer have not been conducted; Klein said that while that is important, other aspects of the disease such as low versus high-volume disease burden, performance status, and disease stage are also critical. Sweeney thinks that publishing results from trials like CHAARTED in peer-reviewed journals can definitely impact clinical guidelines. He added, though, that he knows from conversations that the strength of these trial data has convinced regulators, clinicians, urologists, medical oncologists, and radiation oncologists to adopt the combination therapy in their practices. “It’s going to be easier if it’s on the guidelines and it’s actively being reviewed by the guidelines committees, but it hasn’t reached [that point] yet. I know a number of hospitals have actually put it on their pathways as the preferred choice for high-volume disease and an item to be discussed for patients with low-volume disease. But each country is weighing it out differently,” Sweeney added. When attempting to sequence drugs like abiraterone and enzalutamide, there are strategies to individualize, based on health status, despite the lack of data.
Klein concluded that we have not moved too far from older treatments like ketoconazole, LHRH agonists such as leuprolides, and the trileptins. The current options for patients, per NCCN guidelines, include docetaxel, cabazitaxel, and abiraterone, he said, in addition to the immunotherapy, Provenge. According to Klein, a better understanding of disease genomics, along with additional information on evidence-based therapy canimprove the prognosis for the advanced prostate cancer patient.
Please visit Managed Care Insights on AJMC TV to watch the expert interviews.
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(11):1028-1038.