The current issue of the NEJM has an editorial:
"Metastasis-free Survival — A New End Point in Prostate Cancer Trials" [1]
that I found interesting.
When I failed "curative" therapy 14 years ago, I spent a number of years trying to put off ADT, on the basis that the sooner one begins it, the sooner resistance sets in. In more recent years, I have tried to delay resistance by cycling between ADT & high-normal testosterone. And so, I wonder what the long-term effects are when a drug approved for metastatic PCa is used before mets have appeared?
Intuitively, if one can delay the appearance of mets significantly, it looks like a win for the patient. But the intervention changes the cancer. A two year delay in the appearance of mets might not translate into a two year survival advantage. We need also to consider the effect on cancer-related survival - & overall survival.
In the same issue of the NEJM, we have:
"Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer" [2].
"In this double-blind, phase 3 trial, we randomly assigned, in a 2:1 ratio, men with nonmetastatic, castration-resistant prostate cancer and a PSA doubling time of 10 months or less who were continuing androgen-deprivation therapy to receive enzalutamide (at a dose of 160 mg) or placebo once daily. The primary end point was metastasis-free survival (defined as the time from randomization to radiographic progression or as the time to death without radiographic progression)."
In this group, the median PSA doubling time was 3.7 months.
"The median metastasis-free survival was 36.6 months in the enzalutamide group versus 14.7 months in the placebo group".
Very impressive!
However, "At the first interim analysis of overall survival, 103 patients (11%) receiving enzalutamide and 62 (13%) receiving placebo had died."
Too early to predict what the long-term survival advantage might be.
-Patrick
[1] nejm.org/doi/full/10.1056/N...
Julia A. Beaver, M.D., Paul G. Kluetz, M.D., and Richard Pazdur, M.D.
Earlier this year, the Food and Drug Administration (FDA) approved apalutamide, an androgen receptor inhibitor, for treatment of patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). The approval was based on SPARTAN, a randomized, placebo-controlled trial involving 1207 patients that demonstrated a statistically significant improvement in metastasis-free survival, defined as the time from randomization to either imaging-detectable distant disease or death.1 It was the first drug approval for nmCRPC and the first use of metastasis-free survival as a primary end point to support drug approval.
Nonmetastatic CRPC is a disease state defined by rising levels of prostate-specific antigen (PSA) despite castrate levels of testosterone and the absence of radiographic evidence of distant metastatic disease. The U.S. incidence of nmCRPC is estimated to be 50,000 to 60,000 cases per year.2 PSA screening is common in the United States, and most men with prostate cancer are initially diagnosed with localized asymptomatic disease. Despite early detection and advances in surgical and radiation techniques, disease can recur, and many patients continue to have rising PSA levels after salvage local therapy and subsequent androgen-deprivation therapy. Yet many years may elapse between detection of rising PSA levels and metastasis or death. In one trial of a bone-targeted agent, only a third of control patients had progression to radiographically detectable metastatic disease by 2 years, and median survival was not reached.3 Such long survival periods, along with the availability of multiple subsequent therapies that could confound results, render overall survival an impractical end point and have spurred interest in earlier efficacy end points.
Recognizing growing interest in developing therapies for nmCRPC, the FDA convened an Oncologic Drugs Advisory Committee (ODAC) meeting in 2011 to discuss clinical trial end points and trial designs that might be used to support drug approval.4 The committee examined the risks for metastases, symptoms, complications, and medical interventions associated with disease progression and the practicality of using an overall survival end point in nmCRPC trials. Committee members recognized that the transition from nmCRPC to detectable metastatic disease is a clinically relevant event that can be associated with pain and illness and result in the need for additional interventions. Their recommendations emphasized that though metastasis-free survival is a reasonable end point, ensuring clinical benefit of a drug would require a substantial magnitude of improvement and a favorable benefit–risk evaluation.
In 2012, another ODAC examined the results of denosumab use in a randomized, placebo-controlled trial involving 1432 men with nmCRPC. This trial demonstrated an estimated median improvement of only 4 months in bone-only metastasis-free survival. The committee concluded that this improvement coupled with denosumab’s safety profile did not amount to a favorable risk–benefit profile.4 ODAC members commented that longer metastasis-free survival would be required to justify approval. Subsequently, multiple companies designed trials examining systemic therapies in nmCRPC using metastasis-free survival as the primary end point with overall survival as a coprimary or secondary end point. In addition to SPARTAN, the PROSPER trial evaluated the use of the androgen receptor inhibitor enzalutamide for treatment of nmCRPC; Hussain et al. now report their results in the Journal (pages 2465–74).
Apalutamide was approved on the basis of SPARTAN’s results, which addressed the ODACs’ concerns about the end point. There was a robust improvement in estimated median metastasis-free survival, from 16.2 months to 40.5 months. In addition, time to metastasis and progression-free survival (time from randomization to local or distant metastasis or death) were improved. Results for overall survival were immature at the time of approval but revealed no detriment associated with apalutamide treatment. Apalutamide was well tolerated, and despite a longer median duration of use than placebo, the incidence and severity of adverse reactions were similar to those in the placebo group, with serious adverse events experienced by 25% and 23% of patients, respectively, and grade 3 to 4 adverse events by 45% and 34%. Apalutamide’s tolerability was further supported by patient-reported outcomes revealing no notable adverse signals in symptom or functional effects despite the long treatment duration.
The FDA concluded that apalutamide was safe and effective in nmCRPC. Although the trial population was enriched with patients deemed to have high risk given their PSA doubling time, the large benefit, consistent efficacy across the quartiles of doubling times studied, and favorable safety profile led to recommendations for a less restrictive indication statement. The trial population is clearly described in the labeling, so decisions about what PSA doubling time justifies treatment are left to physicians and patients.
Using metastasis-free survival in nmCRPC trials can present challenges, including prospective specification of imaging methods and assessment frequencies. The end point is assessed with medical imaging, whose increasing sensitivity may increase the sensitivity and specificity of metastasis detection, potentially affecting the interpretation of study results and even changing the baseline characteristics of enrollees over time. In addition, procedures are required for mitigating attrition of participants in the face of “PSA anxiety” caused by rising PSA values. Finally, definitions of metastasis-free survival have been designed to ensure that metastatic events exclude local progression, which is not considered as likely to cause illness and death as are distant bone or visceral metastatic disease. Defining local progression requires careful delineation of methods for evaluating changes in lymph nodes on computed tomography. Since not all studies have excluded local progression in their definitions of metastasis-free survival, the contribution of such progression to overall results must be carefully examined. Efforts are under way to standardize trial design elements including eligibility criteria and end-point definitions in the nmCRPC context,5 and the FDA will continue to collaborate with the drug-development community to address these issues.
Going forward, apalutamide’s approval will make placebo-controlled trials in nmCRPC more difficult to conduct, heralding an era of active controls and add-on trial designs. The magnitude of benefit in a head-to-head trial using apalutamide as a control is likely to be smaller, yet substantial evidence that a similarly safe drug leads to superior metastasis-free survival could still meet regulatory approval requirements. For drugs with greater toxicity, larger improvements in metastasis-free survival should be demonstrated, or a subgroup of patients who are more likely to benefit should be identified. For add-on trial designs, the magnitude of benefit that would be required when combining a new agent with apalutamide would have to be weighed against additive toxicity. Although the FDA has not required demonstration of improved overall survival, continued follow-up for survival and detrimental effects is expected.
Other end points have been used in early-disease settings in which an overall survival end point is problematic. In adjuvant breast- and colon-cancer trials, disease-free or recurrence-free survival is used in studying patients at risk for metastatic disease, and improvements are used to approve drugs while patients are followed for overall survival (in which improvement is not required). Like metastasis-free survival, these end points mark a transition from nonmetastatic to metastatic disease, which triggers subsequent interventions and is associated with an eventual increase in symptoms, toxic drug effects, illness, and death. But though all patients entered into adjuvant breast- or colon-cancer trials are at risk for recurrence, some are cured by local therapy alone and would not otherwise have required treatment; in contrast, men with nmCRPC with rising PSA levels are generally not considered disease-free, and the assumption is that metastatic disease will ultimately be found if they are followed long enough and don’t die from another cause. Moreover, drugs studied for adjuvant treatment of breast or colon cancer have generally already been approved for more advanced disease, whereas apalutamide’s nmCRPC approval was its first.
Previous therapies for metastatic prostate cancer were approved on the basis of survival advantage. Using overall survival as a primary end point will be increasingly difficult, since multiple drugs can be used sequentially for advanced disease, necessitating larger and longer trials and potentially confounding interpretation of results. Similarly, coexisting conditions can influence survival, and non–cancer-related deaths make isolating drug effects problematic unless coexisting conditions are meticulously balanced at randomization.
Whereas radiographic progression-free survival has been standardized as an end point in metastatic settings, there was previously no earlier end point for nmCRPC trials. The FDA has now recognized that a prolonged delay in development of metastatic disease is an objective and clinically relevant measure. Future agents may be approved on the basis of metastasis-free survival only if substantial effects on this transition are demonstrated and the safety profile is acceptable for a medication taken long-term.
[2] nejm.org/doi/full/10.1056/N...
Maha Hussain, M.D., Karim Fizazi, M.D., Ph.D., Fred Saad, M.D., Per Rathenborg, M.D., Neal Shore, M.D., Ubirajara Ferreira, M.D., Ph.D., Petro Ivashchenko, M.D., Eren Demirhan, Ph.D., Katharina Modelska, M.D., Ph.D., De Phung, B.S., Andrew Krivoshik, M.D., Ph.D., and Cora N. Sternberg, M.D.
Abstract
BACKGROUND
Men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising prostate-specific antigen (PSA) level are at high risk for metastasis. We hypothesized that enzalutamide, which prolongs overall survival among patients with metastatic, castration-resistant prostate cancer, would delay metastasis in men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising PSA level.
METHODS
In this double-blind, phase 3 trial, we randomly assigned, in a 2:1 ratio, men with nonmetastatic, castration-resistant prostate cancer and a PSA doubling time of 10 months or less who were continuing androgen-deprivation therapy to receive enzalutamide (at a dose of 160 mg) or placebo once daily. The primary end point was metastasis-free survival (defined as the time from randomization to radiographic progression or as the time to death without radiographic progression).
RESULTS
A total of 1401 patients (median PSA doubling time, 3.7 months) underwent randomization. As of June 28, 2017, a total of 219 of 933 patients (23%) in the enzalutamide group had metastasis or had died, as compared with 228 of 468 (49%) in the placebo group. The median metastasis-free survival was 36.6 months in the enzalutamide group versus 14.7 months in the placebo group (hazard ratio for metastasis or death, 0.29; 95% confidence interval, 0.24 to 0.35; P<0.001). The time to the first use of a subsequent antineoplastic therapy was longer with enzalutamide treatment than with placebo (39.6 vs. 17.7 months; hazard ratio, 0.21; P<0.001; such therapy was used in 15% vs. 48% of patients) as was the time to PSA progression (37.2 vs. 3.9 months; hazard ratio, 0.07; P<0.001; progression occurred in 22% vs. 69% of patients). At the first interim analysis of overall survival, 103 patients (11%) receiving enzalutamide and 62 (13%) receiving placebo had died. Adverse events of grade 3 or higher occurred in 31% of the patients receiving enzalutamide, as compared with 23% of those receiving placebo.
CONCLUSIONS
Among men with nonmetastatic, castration-resistant prostate cancer with a rapidly rising PSA level, enzalutamide treatment led to a clinically meaningful and significant 71% lower risk of metastasis or death than placebo. Adverse events were consistent with the established safety profile of enzalutamide. (Funded by Pfizer and Astellas Pharma; PROSPER ClinicalTrials.gov number, NCT02003924.)
Enzalutamide approved for patients with high risk of metastasis 
Sipuleucel-T boosts survival versus abiraterone or enzalutamide alone in real-world mCRPC analysis
