In high or very high risk prostate cancer, do you utilize combined androgen blockade in patients receiving definitive RT?

Since I had initially posted this, the STAMPEDE investigators have released a new publication reporting the utility of intensified androgen axis blockade (abiraterone ± enzalutamide) in high-risk non-metastatic patients which included high-risk N0 (≈ 60%) and N1 patients (≈ 40%). For this combined population, there was a benefit in 6-yr DMFS of ≈ 13% (HR: 0.53; 82% vs. 69%), OS of ≈ 9% (HR 0.60; 86% vs. 77%), and disease-specific survival of ≈ 8% (HR: 0.49; 93% vs. 85%). 

These numbers represent the benefit in the combined N0 and N1 populations. Regarding the N0 population, a rough estimate of the absolute benefit can be obtained from the data presented in supplementary table 5. Of the N0 patients as it pertains to OS, 105/598 in the control group had an event while 76/599 had an event in the combination therapy group. This yields a raw absolute benefit of ≈ 4.8% (HR 0.7; 95% CI 0.52-0.97). These are raw numbers but for context, the median follow-up in the trial is 6 years. 

The magnitude of the benefit in the N0 patients is definitely less than in the N1 patients, as expected. I believe the additional benefit with abiraterone compares favorably to the yearly absolute benefit from the addition of long term ADT in EORTC 22863 or EORTC 22961, although, of note, the STAMPEDE “high risk N0” patient is higher risk than the NCCN definition (for example, the median PSA for all patients was > 32). I also think that the additional toxicity burden appears relatively modest as compared to the magnitude of benefit demonstrated. Appropriate patient selection is probably key, especially as there may be a lot of stage migration with more advanced staging methods in contemporary clinical practice.

[Prior answer: 6/25/21]

Approximately 25% of the patient population on STAMPEDE had a new diagnosis of very high risk, N0 M0 prostate cancer (defined by at least two of the following: T3/T4, Gleason 8-10, PSA ≥40). The hazard ratio for failure-free survival for this subgroup maintained significance at 0.21 (95% CI 0.15-0.31), while the hazard ratio for OS at 0.75 (95% CI 0.48-1.18) did not.

On the basis of these data, I discuss the addition of abiraterone (2-year duration) with some very high risk patients, most often the young patients with very aggressive disease who voice their preference to be as aggressive as possible even at the increased cost of additional toxicity. In this population, I’m still not clear if abiraterone truly produces superior results when included as a frontline treatment as opposed to being used later in the sequence of therapy. A factor that makes me less enthusiastic is patients with pre-existing significant hypertension which is poorly controlled on multiple antihypertensives based on the toxicity profile of abiraterone. Another situation in which it may be helpful is when staging studies show findings considered to represent a low probability for metastatic disease by radiology in patients with otherwise high baseline risk for metastatic disease in whom you plan to treat using a non-metastatic treatment paradigm.

While improvements in FFS are superior in this M0 N0 (by conventional imaging) very high risk PC population treated with ADT/Abi and RT to the primary as compared to ADT alone, the impact on OS is still not known and we await randomized trials dedicated to this high risk RT-treated population, such as ATLAS and NRG-GU-009 with ADT/apalutamide and ENZARAD with ADT/enzalutamide and DASL-HiCAP with darolutamide, as well as longer term follow up of STAMPEDE for the abiraterone treated men. NCCN presently does not recommend abi in this N0 M0 setting due to the lack of a known impact on MFS or OS. However, I agree that the major effect on FFS going out 5 years is remarkable and is thus a reasonable option to consider in appropriately selected men who are fit, willing to accept the added risks and potential costs of abiraterone/ADT for 2 years in this RT setting. 

Prior studies utilizing combined androgen blockade in the adjuvant or neoadjuvant surgical setting have similarly failed to demonstrate an overall survival advantage (McKay et al., PMID 30811282). At this time, there is no definitive evidence of survival benefit with this approach. However, there is failure free survival. It is reasonable to discuss those anticipated results with patients. I have also used this approach in younger patients that generally prefer a more aggressive approach. The ERA-223 trial (Shore et al., PMID 32404868) and publication of PEACE-III (see ASCO 2021) highlight that we need to pay attention to bone health though, particularly in the setting of more aggressive prostate cancer treatment. 

Yes, I do use combined ADT, typically 12 mo in an attempt to take advantage of other endpoints of prostate treatment failure and success e.g., BFS, PFS, DFS, especially LC, etc. I would caution putting too much weight into OS with prostate cancer as long-term ADT following relapse, continuous or intermittent, definitely takes its toll and so many men live long while on hormones having poor QoL. In fact, many men die as a consequence of ADT accelerating cardiovascular dz, diabetes, strokes, bone fragility with falls, cognitive/dementia, etc. In fact, I would argue that the death rate of prostate cancer is higher than the data shows worldwide as men are typically not counted as prostate deaths when they die from hormone-related morbidities (except for all-cause mortality).

Absolutely. Dual androgen blockade requires some clarification. What agent are we talking about? Historically, we would have been referring to bicalutamide which I use in all my patients I think to warrant it, even in some unfavorable intermediate-risk cases. 

However, the reason is not that eloquently established in other answers about the benefit of abiraterone or enzalutamide (as I call them second generation androgen deprivation) with disease-specific outcomes. Rather that 10% of men may not be castrated when I am doing my radiotherapy. I extrapolate from the trend from RTOG 9413 for concurrent RT with ADHT with pelvic nodal treatment and start them 2 mo after ADHT is initiated. I continue bicalutamide for 4 full months and then I check PSA and testosterone after treatment. If they are adequately low on their testosterone, I don’t continue. 

For LN positive prostate cancer, I think there is clear established benefit of second generation ADHT as they were included in randomized control trials utilizing them.

I would hesitate promoting NCCN guidelines for prostate cancer as an “end all be all” resource given the lack of even mentioning oligometastatic prostate cancer having some rationale for definitive therapy to the primary and all oligometastatic sites (including bulky PA LN involvement). This is what I would consider a reasonable standard of care for all cancers at this point.

I don't use casodex 50mg with LHRH agonist or antagonist. I have been using LHRH ag/antag with Abi per STAMPEDE platform in HRN0 any/N1. I have also occ used Abi alone without LHRH in patients intolerant of dual. Test still castrate and tolerance improved.