Xtandi (enzalutamide) +ADT slows metastases in recurrent men

It is always difficult for a recurrent patient (rising PSA after prostatectomy, radiation, or both) with no metastases to decide when to start salvage hormone therapy and, if so, which hormone therapy. That is the question that the EMBARK randomized clinical trial (RCT) sought to answer. We have recently seen that the PRESTO trial proved that a one-year course of ADT+ apalutamide (Erleada) significantly delayed biochemical progression compared to ADT alone.

EMBARK Protocol

This was a huge trial with 1,068 patients treated at  256 centers around the world. To qualify, patients had to have:

• Biochemical progression after attempted curative treatment with prostatectomy (RP), radiation (RT), or both (SRT).
• PSA≥ 1 ng/ml if RP; ≥ 2 ng/ml above nadir if RT
• PSA doubling time (PSADT) ≤ 9 months
• No metastases on conventional imaging

Patients were randomized to one of three groups:

1. enzalutamide + ADT with leuprolide (combination)
2. ADT (leuprolide)-only (the control group)
3. enzalutamide-only (enza monotherapy)

The control group received a placebo (blinded). The third group was not blinded. There were periodic PSA tests, but neither patients nor their physicians were privy to the PSA results.

One of the goals of the trial was to see which treatment strategy allowed for the longest hormone-therapy vacation (see this article about intermittent ADT- Setting 3). Patients in all 3 groups were given a hormone therapy vacation as long as their PSA became undetectable (< 0.2) by week 36. The vacation ended when PSA rose to ≥ 2.0 (if previous RP) or ≥ 5.0 (if no previous RP).

Oncological Results

After 5 years of follow-up, the early results were reported by Neal Shore at an ASCO meeting: 

• Relative to the control group, the incidence of distant metastases was reduced by 58% by combination therapy, and by 47% by enza monotherapy.
• Overall survival results are not yet mature, but so far mortality has been reduced by 41% by combination therapy, and by 23% by enza monotherapy
• Time to PSA progression (castration resistance) was increased by 93% by combination therapy, and by 67% by enza monotherapy.
• Time to chemotherapy was increased by 64% by combination therapy, and by 46% by enza monotherapy.

Vacation (iADT) Results

• The percentage of patients that achieved undetectable PSA (< 0.2) by week 36 of therapy and were able to take a vacation was 91% for the combo, 68% for the control, and 86% for enza-monotherapy.
• The vacation lasted for 20 months for the combo, 17 months for the control, and 11 months for enza-monotherapy
• Testosterone only reached about half of baseline during the vacation in the combination and control groups. Testosterone rose to well above baseline in the enza-monotherapy group.

Toxicity Results

• Serious or worse adverse events attributable to medications occurred more often in the groups given enzalutamide (18% of the combo and 16% of the enza monotherapy groups compared to 9% in the leuprolide-only group).
• Fatigue was the most common side effect and occurred more often with enzalutamide (47% for the monotherapy, 43% for the combination) than with leuprolide alone (33%)
• Hot flashes much less often occurred in the enza-monotherapy group (22%) than in the combination group (69%) or the leuprolide-only group (57%).
• Gynecomastia/nipple pain was prevalent in the enza-monotherapy group (45%/15%)
• All other side effects were experienced about equally.

Conclusions

• If one is recurrent with PSADT≤ 9 months, treatment with a combination of Lupron and Xtandi improves oncological outcomes
• If the trial were started now, everyone would get a PSMA PET/CT. It is likely that most would detect distant metastases.
• Intermittent hormone therapy is likely to provide the longest vacation if one is getting the combination, but the quality of the (half as long) vacation may be better with enza-monotherapy because of greater testosterone recovery.
• Enzalutamide increases many side effects, including fatigue.
• Enza-monotherapy is less likely to cause hot flashes, but more likely to cause gynecomastia.

Recurrent PC (non-metastatic, hormone sensitive) after curative therapies exhausted? Here are some clinical trials to look at.

A perplexing situation is what to do after one has tried one or more potentially curative therapies (e.g., prostatectomy plus salvage radiation including pelvic lymph nodes), and there are no detectable metastases, but PSA keeps rising. The TOAD randomized clinical trial demonstrated that survival is improved by starting on hormone therapy (intermittent or continuous) as soon as recurrence is observed. Chemo has not proved to increase survival until after multiple metastases are detected (CHAARTED). Waiting for metastases to appear and spot treating them  has not proved to be beneficial either (see this link).

There may be hope in participating in clinical trials. There aren't many. There is a trial for the earlier use of Xtandi therapies, as well as trials for novel therapeutics, like apalutamide and Prostvac, which have been very promising in early trials. Here's a current list that you may wish to discuss with your medical oncologist:

Advanced hormonal therapies:

Apalutamide:at University of Texas, Houston (a larger trial is no longer recruiting)
Apalutamide/ degarelix/abiraterone at 8 locations
Xtandi at 172 locations
Xtandi at University of Colorado, Denver

Immunotherapy/PARP inhibitor:

Prostvac at NIH
Durvalumab + Olaparib at MSK
Olaparib - recurrent - Johns Hopkins & Thomas Jefferson U.

MAO inhibitor:

Phenelzine at USC

Salvage whole-gland cryoablation after radiation therapy failure

At the 17^th International European Association of Urology Meeting, Joseph Chin of the University of Western Ontario presented his analysis of outcomes of 157 patients treated with whole-gland salvage cryotherapy after primary radiotherapy failure between 1995 and 2004. After a median followup of 117 months:

• ·      10-year overall survival was 76%
• ·      10-year metastasis-free survival was 74%.
• ·      Median biochemical disease-free survival was 56 months.
• ·      10-year biochemical disease-free survival was 34%.
• ·      15-year biochemical disease-free survival was 23%.
• ·      Of the 179 complications, 22 (12%) were serious.

While more than 3 in 4 men had a biochemical recurrence after salvage cryotherapy, it’s not at all clear whether any salvage therapy on this group of patients could have increased survival any better or with fewer complications. As far as I’m aware, this is the longest followup that has been reported in a salvage cryotherapy study, but, paradoxically, its greatest strength is also its greatest weakness. Many of the men treated in this study were selected for salvage treatment before we had advanced imaging techniques that might have identified small distant metastases in many of them. Also, cryotherapy has benefitted from technological advances that have reduced morbidity considerably.

There are many outstanding questions:

• ·      How should patients be selected for salvage therapy after radiation?
• ·      Can we use advanced imaging to eliminate those patients in whom distant metastases have already occurred?
• ·      Did the salvage therapy delay progression?
• ·      Is there a survival advantage to salvage whole-gland cryoablation vs. focal or hemi-gland cryoablation?
• ·      Is there an advantage in terms of treatment morbidity to salvage whole-gland cryoablation vs. focal or hemi-gland cryoablation?
• ·      How does salvage cryo compare to other ablative salvage therapies, salvage radiotherapies, or salvage surgery after radiation failure?