For metastatic hormone-sensitive prostate cancer, six cycles of docetaxel in addition to androgen deprivation is a new acceptable standard of care.
—Evan Y. Yu, MD
Several studies reported at this year’s ASCO Annual Meeting address gray areas in the management of prostate cancer, according to Evan Y. Yu, MD, Associate Professor at the University of Washington and the Seattle Cancer Care Alliance. “In prostate cancer, probably the most excitement has happened within the last 4 years. We have really made a lot of great changes, and I feel fortunate to be in this field,” he commented at the Best of ASCO meeting held in Seattle, where he recapped some of the key abstracts and shared his own perspectives.
Deferring Androgen Deprivation After Relapse
After treatment of clinically localized prostate cancer, management of biochemical recurrence, indicated by rising prostate-specific antigen (PSA), remains one such gray area, generating anxiety for patients and clinicians alike, according to Dr. Yu. In an analysis of data from CaPSURE, investigators compared immediate initiation of androgen-deprivation therapy vs deferred initiation—defined as waiting 2 years or until symptomatic, imaging, or PSA doubling evidence of metastases—in men who had a PSA-only relapse.1 Results showed statistically indistinguishable 5- and 10-year rates of all-cause mortality and prostate cancer–specific mortality between the two strategies.
“The key here is this probably doesn’t change standard of care, whatever standard of care is. And in the United States, we probably tend to get a little nervous when the PSA rises high or is rising fast, and start [androgen-deprivation therapy] before the patient has metastatic disease,” Dr. Yu commented. However, he added, most of the patients studied had low-risk disease; at 10 years, only 30% had died and merely 10% had died of prostate cancer.
“I’m not sure what intervention might improve upon whatever other intervention we use when most of your patients don’t die of the disease. They are going to live a long time and die of other causes,” he said.
An ongoing collaborative phase III trial in Australia2 exploring the optimal timing of androgen-deprivation therapy initiation in this context may help provide more guidance in this area. However, “my concern even with this phase III trial is that the eligibility criteria are loose. It’s not picking the highest-, highest-risk patients. I think to make an impact here, you have to pick those patients,” Dr. Yu said.
Chemohormonal Therapy for Newly Metastatic Disease
The randomized phase III CHAARTED trial compared chemohormonal therapy with hormonal therapy in men with hormone-sensitive newly metastatic prostate cancer.3 The rationale came in part from the observation that adding chemotherapy had a benefit in castration-resistant metastatic disease, so it might be similarly efficacious if moved earlier (see sidebar, “Pros and Cons of Early Chemohormonal Therapy” on page 15).
Patients with radiographically detectable metastases were randomized to continuous androgen-deprivation therapy plus docetaxel or androgen ablation alone. The primary endpoint of overall survival was significantly better with chemohormonal therapy, with a median 13-month gain (hazard ratio [HR] = 0.61); subgroup analyses suggested benefit was restricted to patients with high-volume disease, defined as presence of visceral metastases or four bone lesions, at least one of them outside the axial skeleton, with a median 17-month gain in overall survival in this subset (HR = 0.60).
Dr. Yu concurred with the authors that these data are practice-changing. “For metastatic hormone-sensitive prostate cancer, six cycles of docetaxel in addition to androgen deprivation is a new acceptable standard of care,” he stated. And cost analyses are also favorable for this chemohormonal combination, given that docetaxel has come off patent.
At the same time, Dr. Yu noted that patients with low-volume disease have had shorter follow-up, and the definition of high-volume disease is somewhat arbitrary (see sidebar, “What Constitutes High-Volume, Extensive Disease?” on page 16). He also questioned the emphasis placed on the negative subgroup finding in patients with low-volume disease, given that conventional wisdom is to deemphasize positive subgroup findings in negative trials. “We obviously need to see the quality-of-life data, and we anticipate there will be toxicities from the docetaxel, but it is only six cycles,” he said.
New Data on Castration-Resistant Prostate Cancer
A randomized phase III trial of orteronel (formerly TAK-700) plus prednisone in chemotherapy-naive patients with metastatic castration-resistant disease yielded disappointing results.4 There was a 5.1-month radiographic progression-free survival benefit (HR = 0.71) but no significant overall survival benefit.
“Many people have noted that if these [orteronel] trials were done a year, a year and a half earlier, without so much confounding from all the other subsequent therapies that prolong survival in prostate cancer, that they would have been positive,” he noted. But given the data, “orteronel development has basically ceased.”
That said, orteronel trials being conducted by cooperative groups like SWOG and the Radiation Therapy Oncology Group are still ongoing.
Biomarkers are an area of intensive research in metastatic prostate cancer, according to Dr. Yu. “We definitely need predictive biomarkers in prostate cancer—we need our EGFRs, our HER2s, our KRASs. And variant 7 of the androgen receptor (AR-V7) is potentially a very promising biomarker,” he commented. This splice variant allows the internal domain of the receptor to be constitutively active, even without a ligand, making it a possible resistance mechanism.
In a study reported at the Annual Meeting, investigators assessed the presence of AR-V7 in circulating tumor cells from patients with metastatic castration-resistant prostate cancer.5 Compared with counterparts who were negative for this variant, patients who were positive had a dramatically higher risk of progression or death if treated with abiraterone (Zytiga; HR = 16.5) or enzalutamide (Xtandi; HR = 8.5).
Additionally, prevalence of AR-V7 appeared to increase with the extent of exposure to hormonal agents. It was 11.6% in patients who had received neither drug, 25.0% in those who had received only enzalutamide, 51.2% in those who had received only abiraterone, and 66.7% in those who had received both.
“AR-V7 warrants further evaluation as a potential predictive biomarker. A randomized controlled study to determine predictive value may show AR-V7 to be a negative predictor of response to these therapies,” Dr. Yu commented. “The bar is probably lower for getting this biomarker approved, more like a KRAS, because it’s not selecting you for therapy, it is selecting you away from certain therapy.” These data could also help inform development of inhibitors of the intracellular N-terminal domain of the androgen receptor, he added. ■
Disclosure: Dr. Yu has received research funding from Bristol-Myers Squibb, Dendreon, Janssen, and OncoGeneX and consulting honoraria from Bayer, Dendreon, Janssen, Medivation/Astellas, and Sanofi-Aventis.
1. Garcia-Albeniz X, Chan JM, Paciorek AT, et al: Immediate versus deferred initiation of androgen deprivation therapy in prostate cancer patients with PSA-only relapse. ASCO Annual Meeting. Abstract 5003. Presented June 1, 2014.
2. Androgen deprivation therapy in treating patients with prostate cancer. Available at clinicaltrials.gov, identifier NCT00110162, last updated August 6, 2013.
3. Sweeney C, Chen Y-H, Carducci MA, et al: Impact on overall survival (OS) with chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic prostate cancer (mPrCa): An ECOG-led phase III randomized trial. ASCO Annual Meeting. Abstract LBA2. Presented June 1, 2014.
4. De Wit R, Fizazi K, Jinga V, et al: Phase 3, randomized, placebo-controlled trial of orteronel (TAK-700) plus prednisone in patients (pts) with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) (ELM-PC 4 trial). ASCO Annual Meeting. Abstract 5008. Presented June 1, 2014.
5. Antonarakis ES, Lu C, Wang H, et al: Androgen receptor splice variant, AR-V7, and resistance to enzalutamide and abiraterone in men with metastatic castration-resistant prostate cancer (mCRPC). ASCO Annual Meeting. Abstract 5001. Presented June 1, 2014.
Questions abound when it comes to the optimal timing and sequencing of chemotherapy in metastatic prostate cancer, according to Dr. Yu. For example, arguments could be made both for using it earlier, while disease is still hormone-sensitive, or later, after hormonal resistance emerges.
There is considerable debate about moving chemohormonal therapy to an earlier point in the treatment of prostate cancer, at the time of initial diagnosis of metastases, according to Dr. Yu. In the pro column, “You might hit those de novo testosterone-independent clones if they exist.” Additionally, ...
"I'm not sure what extensive disease really is, but in some patients, when you see it, you really recognize it. In other patients, it’s not 100% clear,” Dr. Yu commented (Fig. 1). Some patients with multiple medium or large lesions in bone would clearly meet the definition used in the CHAARTED...