Although guideline organizations have now incorporated the results of major clinical trials into treatment paradigms, much controversy remains over how best to sequence therapies in prostate cancer.
Celestia S. Higano, MD, FACP
In the ever-evolving treatment landscape in metastatic prostate cancer, healthcare providers have more options that ever before. Although guideline organizations have now incorporated the results of major clinical trials into treatment paradigms, much controversy remains over how best to sequence therapies, according to experts who participated in a recent OncLive Peer Exchange.
In recognition of this complexity, moderator Raoul S. Concepcion, MD, FACS, and colleagues took a case-based approach to explore the ways in which oncologists and urologists can employ newly acquired evidence to manage patients whom they encounter in their practices. The Peer Exchange session, entitled “Integrating Prostate Cancer Trial Findings Into Practice: A Case-Based Discussion,” incorporated four cases, two of which are presented here.
Newly diagnosed patient with hormone-naïve, confirmed metastatic prostate cancer
Scenario: A 58-year-old African American male, PSA 251.8 ng/dL, presents to emergency department in January 2015 with abdominal and lower back pain
Although it may be unusual for clinicians to encounter newly diagnosed patients with high-grade prostate cancer metastatic to the bone, researchers have noted an increase in patients presenting with high-risk disease since the US Preventive Services Task Force changed its recommendations on prostate cancer screenings,1 noted Joseph F. Renzulli, II, MD, FACS.
Raoul S. Concepcion, MD
He said he is seeing more high-grade cancers in his urology practice.
In the case of a newly diagnosed patient with hormone-naïve high-grade metastatic prostate cancer, initiating therapy with a luteinizing hormone-releasing hormone antagonist (LHRH) would be appropriate, said Renzulli. “We tend to use an antagonist, in this case to get rapid suppression of testosterone within about 3 days, and then based on that, we watch for his PSA response and symptomatic response to that.”
Although androgen deprivation therapy (ADT) has been the standard treatment, Concepcion noted that new evidence suggests this patient could benefit from a more aggressive approach.
Data from the CHAARTED trial suggest that early chemotherapy should be considered for this patient, said Daniel P. Petrylak, MD. Results from CHAARTED are not yet published, and were first presented at the 2014 ASCO Annual Meeting.2
Joseph F. Renzulli, II, MD, FACS
CHAARTED demonstrated that upfront chemo-therapy with docetaxel added to ADT improved survival over ADT alone in men with hormone- sensitive metastatic prostate cancer.2 The study found there was a median overall survival (OS) of 57.6 months with the addition of docetaxel compared with 44 months with ADT alone (HR, 0.61; P = .0003).2 The benefit was more pronounced in patients with high-volume disease. Petrylak said that it does make sense to add another agent to ADT in high-volume disease, given that there are theoretically more genetic abnormalities, more mutations, and a higher chance of drug resistance. However, the mechanism by which patients achieved the added survival benefit in this subgroup is not known.
“How docetaxel is working in this situation, whether it’s through androgen receptor— mediated mechanism or some other mechanism that we’re not sure of, and why we are seeing such great differences, is not clear at this point,” he said.
A large European study presented at the 2015 ASCO Annual Meeting confirmed the findings in the CHAARTED study. STAMPEDE examined the survival benefit with adding various treatments to the standard of care with ADT.3
Adding docetaxel to standard hormone therapy increased median OS by 10 months among men with newly diagnosed advanced prostate cancer (77 months vs 67 months, respectively; HR, 0.76; P = .003).3 Results from STAMPEDE also showed a nonsignificant benefit with the addition of zoledronic acid.3 The trial is ongoing and includes nine treatment arms. ADT plus celecoxib, abiraterone, or enzalutamide are among the therapies being examined.
Daniel P. Petrylak, MD
Another European study, GETUG-AFU, did not find a survival benefit with docetaxel as add-on therapy to ADT in patients with hormone-sensitive metastatic disease.4 However, the GETUG-AFU trial was much smaller than the STAMPEDE and CHAARTED trials and had fewer patients with high-volume disease, commented Celestia S. Higano, MD, FACP. Despite the findings in GETUG-AFU, the overall evidence points to a benefit associated with initiating upfront chemotherapy along with ADT, according to Higano. “I think when you see two trials pointing to survival benefit in this population of patients, we have to really say, okay, maybe there’s some issues here and there but we have to go with this data,” she said.
Renzulli noted that, for a patient who has high-volume, high-grade disease with positive localized nodes in the pelvis, he had been administering hormone therapy along with radiation based on data available before the STAMPEDE trial results were announced. “I guess the question back to the oncologists would be now with this data, would you extrapolate to node-positive disease and if so, how many nodes would it have to be a certain criteria?” asked Renzulli. Petrylak and Higano agreed that more data are needed to confirm a benefit in node-positive disease; ongoing clinical trials may help answer these questions.
Patient with mCRPC progressing on multiple therapies and poor performance status or comorbidities
Scenario: A 70-year-old white male, PSA 5.7 ng/mL
The American Urological Association (AUA), National Comprehensive Cancer Network (NCCN), and ASCO guidelines for the treatment of advanced prostate cancer need frequent updates due to the increasing amount of clinical data.
One of the studies incorporated in the 2015 AUA guideline was the PREVAIL trial,5 which showed improved overall and radiographic progression-free survival with enzalutamide versus placebo in men with metastatic prostate cancer whose disease progressed after ADT therapy, explained Christopher P. Evans, MD, FACS. Also new in the guidelines this year, are updated survival data from the COU-AA-302 trial in which abiraterone plus prednisone significantly improved OS to 34.7 months (P = .0033) compared with 30.3 months placebo plus prednisone in men with asymptomatic or mildly symptomatic chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC).6
In light of these new data, Concepcion presented a case study that highlights one of the most challenging scenarios in advanced prostate cancer. The patient has mCRPC, has progressed on multiple therapies, and is taking opioids to control pain. Based on his seizure history, this patient should not have enzalutamide, noted Petrylak. The patient should receive upfront chemotherapy with docetaxel, which has been shown to have an analgesic effect within one week. Data from the TAX 327 trial showed that approximately 35% of patients with advanced, hormone-refractory prostate cancer had significant pain reduction with docetaxel (P = .01).7
Higano agreed that chemotherapy is appropriate in this patient. She noted that it is important to understand whether the patient’s poor performance status is because of his comorbidities or because of cancer-related symptoms. “Even some of our colleagues, I think, do not treat patients who have bad performance status due to their cancer. These are the patients who frequently have the most gratifying responses to chemotherapy or some of the other treatments we use,” she said.
In response to a question about the use of radium-223 in this patient, Higano referred to the ALSYMPCA trial, which showed that radium- 223 is effective in patients with mCRPC, regardless of previous docetaxel use.8 Median OS was 14.9 months with radium-223 versus 11.3 months with placebo.8 Radium-223 was associated with a 30% reduction in the risk of death (HR, 0.70; P <.001).8 She said she would likely not treat this patient with radium-223 because he is symptomatic with mainly bone disease. If he were asymptomatic, she would not hesitate to use it. In her experience, symptoms are not immediately resolved with radium-223. “I want to treat this [patient] right away with something that I’m fairly confident will either work well or it won’t work at all,” she said. Higano cautioned against administering radium-223 with chemotherapy because the combination has been shown to be very myelosuppressive.
Christopher P. Evans, MD, FACS
After chemotherapy, if the patient’s PSA rises and there is evidence of new lesions and new soft tissue disease, there are two oral options to consider, noted Renzulli. Normally, if the patient has visceral disease, Renzulli would lean toward enzalutamide. In this case, especially because of the history of seizure, abiraterone with prednisone may be the better option, he stated. It is also important to offer palliative care to help the patient manage his pain.
Abiraterone also can be given in combination with cabazitaxel. “We presented some data last year looking at the combination of abiraterone and [cabazitaxel], and you could give both of those at full doses fairly safely. So that’s I think something also that may be in the future that we may be able to avoid the sequencing issue with,” stated Petrylak.
Evans said there are a number of factors to consider in choosing therapies.
If the patient did not tolerate the chemotherapy well, it may be best to start with abiraterone; if he was able to handle the toxicities, then cabazitaxel would be a possibility. “I wouldn’t say there’s no right answer,” he said. “I would say they’re all right answers.”