At the 2018 Genitourinary Session of the American Association of Clinical Oncology two presentations reported similar findings which offer management guidance for men whose PSAs are rising despite androgen suppression but have no objective evidence of metastatic spread. For men with metastases Zytiga and Xtandi are commonly prescribed, but to date there have been no approved treatments for therapy at the nonmetastatic CRPC stage.
THE IMPORTANCE OF PSA DOUBLING TIME (PSADT) AND METASTASES-FREE SURVIVAL (MFS)
There has been a steady effort to establish PSADT as an indicator of cancer aggressiveness and its relationship with the development of metastases. A classic contribution to this issue was made by Antonarakis, Eisenberg et al.: “The natural history of metastatic progression in men with prostate-specific antigen recurrence after radical prostatectomy: long-term follow-up,” BJU Int, 2012 Jan. Their goal was to define clinical prognostic factors modifying metastatic risk. Their work involved men with biochemical failure after primary treatment, not in men with CRPC.
Their findings validated the importance of PSADT as a surrogate of cancer aggressiveness and as a predictor of the duration of MFS, as defined in their study with technetium bone scans and CT scans. Although the development of newer imaging techniques is increasing the sensitivity for identifying metastases, MFS is a useful endpoint for evaluating therapy effectiveness. Based on the same data of BJU study, a report by Schweizer, Antonarakis, Eisenberger et al., Ann Oncol, 2013, established MFS as a surrogate for overall survival. This association has been supported by other researchers.
Briefly, in the BJU report the researchers found that a clinically meaningful stratification resulted by subgrouping PSADTs into four subcategories: <3.0 vs 3-9 vs 9-15 vs >15.0 months. The following figures for MFS are taken from the graph, Fig.3, and are offered only as a representation of the strong influence of PSADT on median time to metastases: i.e., 1 month; 4, 9, and 15 months, respectively for the above subgroups.
These studies provide support for the use of PSADT in both of the ASCO 2018 studies evaluating the effect of the addition of apalutamide or enzalutamide (with continued ADT) on duration of MFS. Each stratified their observations into two categories: PSADT less than 6 months vs 6-10 months.
For reference: This is the link to the Memorial Sloan Kettering calculator for PSADT: https://www.mskcc.org/nomograms/prostate/psa_doubling_time
Both apalutamide and enzalutamide are “antiandrogens” and are in the same category as bicalutamide (Casodex), but compared to bicalutamide, both are 5-10 times more effective in blocking the access of testosterone and dihydrotestosterone to their requisite binding site on the androgen receptor. Apalutamide and enzalutamide are structurally very similar. Apalutamide compared to enzalutamide, displays less brain penetration and may be associated with a lower incidence of seizures, already a very uncommon adverse effect of enzalutamide.
Of note: Abiraterone has not been FDA approved for use in men prior to the diagnosis of metastases. However, in a subgroup (28% of 1917 men) of the STAMPEDE trial (James et al. NEJM. June 2017) men with high-risk cancer beginning androgen suppression were treated with either abiraterone/pred + ADT vs ADT alone. At 4 years follow-up 90% of men on combination therapy were failure-free compared to 60%. These findings suggest that this combination therapy is also more effective in improving failure-free survival even when employed at an early hormone sensitive stage of the disease. (The high-risk men in following studies were already castration-resistant.)
THE TWO TRIALS REPORTED AT ASCO GU 2018:
A similar message is clear in both reports:
In men with nonmetastatic CRPC whose PSA doubles in less than 6 months, treatment with either apalutamide or enzalutamide added to the continuation of androgen suppression delayed the development of metastases compared to only continuing ADT, i.e. Lupron, Firmagon or castration. Although the data needs to mature, it appears that survival is also prolonged.
1.) SPARTAN Trial: “A phase 3 double-blind, randomized study of apalutamide (APA) versus placebo (PBO) in patients with nonmetastatic castration-resistance prostate cancer,” Small et al. Feb 8, 2018.
Eligibility for this trial of 1207 men required a “rising PSA despite castration-resistant testosterone (testosterone <=50 ng/dL) and PSADT <=10 months. The primary end point was MFS, defined as the time from randomization to first radiographic distant metastasis or death.” ADT was continued in both groups.
Findings: The median PSADT was < 5 months in both groups.
- “Apalutamide decreased the risk of distant metastases or death by 72% with a median MFS of 40.5 mo (combination) vs 16.2 mo for those men continuing on ADT (plus placebo) alone. (“The benefit was see in all subgroup analysis except black men,” Eric Small).
- Time to PSA progression (at median follow-up of 20.3 months): not reached (combo) vs. 3.7 months (ADT alone)
- The majority of men failing treatment in both arms were offered abiraterone though the trial.
- Overall Survival (interim analysis): for the combination OS not reached (but a ~30% reduction suggested) compared to placebo, 39 months.
- “Adverse events were slightly higher in the apalutamide arm … serious adverse events (25% vs 23%).”
2.) PROSPER Trial: “A phase 3, randomized, double-blind, placebo-controlled study of enzalutamide in men with nonmetastatic castration-resistant prostate cancer,” Hussain et al. Feb 8, 2018.
Eligibility in this 1401 man trial required nonmetastatic CRPC with a PSADT of < 10 months and a PSA > 2 ng/mL. The primary endpoint was MFS.
Findings: The median PSADT was < 4 months in both groups.
- Enzalutamide added to ADT significantly prolonged MFS to a median of 36.6 months vs 14.7 for men continuing on ADT alone, representing a 71% reduction in the risk of developing metastases.
- Time to PSA progression: 37.2 months (combo) vs. 3.9 months (ADT alone).
- Overall survival (interim analysis): not reached but favoring enzalutamide arm by ~20%.
- Serious adverse effects (24% vs 18%) were more common in the combination therapy group.
As demonstrated in both the PROSPER and the SPARTAN trials, treatment with either apalutamide or enzalutaminde, both with continued ADT, in men with nmCRPC delays the development of metastases compared to ADT alone. Enzalutamide has already received “priority review” for this indication by the FDA. When both are approved for use in the nmCRPC setting, these two regimens are likely to become the new standard of care for this phase of the disease.