Thursday, September 21, 2023

Pluvicto does not work better if used before docetaxel in mCRPC

We have seen (see this link) that Pluvicto works about the same as Jevtana in men who are metastatic and castration-resistant (mCRPC) and who have already used docetaxel and failed one advanced hormonal therapy (abiraterone or enzalutamide). But would there be any advantage in mCRPC men who have not yet had any chemo?

Satapathy et al. sought to answer this question. They randomized 40 men to either docetaxel or Pluvicto who were chemo-naive, and mCRPC.

After a follow-up of 33 months they found that both groups survived for 15 months, based on the therapy they were intended to get. When they looked at the therapy they actually got, there was still no statistically significant difference (19 months for Pluvicto vs 15 months for docetaxel).

This was a very small Phase II trial, so it is possible that there would have been a significant difference in a larger trial. However, while there are trials that randomize mCRPC patients to 177LuPSMA or 2nd line hormonal (see this link), I am not aware of any other trials exploring the sequencing of docetaxel or Pluvicto in chemo-naive mCRPC patients.

Saturday, May 6, 2023

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.

  • 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.

Thursday, April 27, 2023

Intermittent ADT

 No one likes Androgen Deprivation Therapy (ADT). Even in the short term, there are hot flashes to contend with, fatigue, and loss of libido. Longer term, there may be cardiovascular side effects, bone loss, fat gain, brain fog, low red blood cell count, blood sugar dysregulation, and mood swings. What are the potential risks and benefits of taking occassional vacations (called "intermittent androgen deprivation therapy"- iADT) from continuous androgen deprivation therapy - cADT?

For a discussion of all randomized trials of iADT vs. cADT, see this link. I will focus on a few of the most important trials that had homogeneous patient populations and had the longest follow-up. Patients must focus on the situation (called the "setting") they currently find themselves in - the advisability of using iADT differs with the setting.

I. Settings

1.  Active Surveillance

Active Surveillance for low- and some favorable intermediate-risk patients requires no interventions. There have been several trials of short-term use of hormonal therapies - see this link under the subheading "I. Systemic Hormonal Therapies." All trials suffer from "lead time bias," which means that progression is not detected until after the hormonal therapy wears off. Nothing is gained: one only buys time onactive surveillance with time on the hormonal therapy.

2. Localized High Risk, Pelvic Lymph Node-only (N1), or Salvage Radiation

ADT in these situations must be continuous. For localized high-risk prostate cancer (PCa), ADT must continue for 12 months if brachy-boost therapy is given, and 26 months if external beam therapy is given (see this link). If there are cancerous pelvic lymph nodes detected by conventional imaging, 3 years of ADT and 2 years of abiraterone is standard-of-care (see this link). If detected on PET scan only, there is less data. If it is adjuvant ADT given with salvage radiation, 4 months to 2 years may be used (see this link)

Stopping and restarting ADT is like stopping and restarting antibiotics - it selects for the most resistant strains. The resistant strains are killed by sustained use of ADT and possibly more intensive hormone therapy. If unleashed by a vacation, they are not easily killed by simply adding more ADT. One can cause an aggressive, resistant type of PCa to predominate by using iADT in this situation.

3. Recurrent PCa

It is controversial whether to use ADT at all when PCa detected only by rising PSA after attempted curative treatment. The PRESTO randomized clinical trial showed that in patients with rapid PSA doubling time, a year of intensive hormone therapy (with apalutamide) could delay progression for a long while. The EMBARK randomized clinical trial showed that in similar patients, treatment with enzalutamide slowed castration resistance and the incidence of metastases.

Crook et al. reported the results of a Canadian randomized clinical trial (NCIC- CTG PR.7) among 1,386 men with PSA recurrence after primary radiation therapy. They were randomized to iADT or cADT. The iADT protocol was:

  • no one had detectable metastases on a bone scan/CT
  • 8 months on, 8 months off
  • Vacations continued unless PSA during the on cycle failed to fall below 4 ng/ml, or if the lowest PSA was 1 ng/ml above the nadir reached in the previous cycle, or if there was evidence of castration resistance (3 consecutive increases during an on cycle or clinical evidence).

After 7 years of follow-up:

  • There were no significant differences in adverse events, except for hot flashes, libido, and urinary symptoms.
  • Testosterone recovered to baseline in 35% in the iADT cohort. 
  • Only 29% of men who were potent at baseline had a recovery of potency
  • Median survival was 9.1 years for cADT vs 8.8 years for iADT (not statistically different)
  • Median prostate cancer mortality was 18% for iADT and 15% for cADT (not statistically different)
  • After adjustment to allow for time to get back on ADT and monitor PSA for 3 consecutive rises (Figure S5), eliminating ascertainment bias, there was no difference in time to castration resistance.
  • Those who achieved lower nadir testosterone in the first year had lower PCa-specific mortality (see this link). Those with a higher nadir testosterone, developed castration resistance sooner and died sooner.

For recurrent men, iADT may give equal oncological results. Results may be improved, however, with more effective androgen deprivation.

4. Recurrent (Stage M0) or Locally Advanced (Stage N1) HSPC

Patients in these situations would rarely opt for treatment with ADT only, because they can potentially be cured with salvage radiation and adjuvant (limited term) ADT. 

In the ICELAND trial, 701 recurrent (no distant metastases) or locally advanced (metastases only in pelvic lymph nodes - Stage N1) patients from 20 European countries were randomized to receive iADT or cADT. The protocol was:

  • All patients had ADT with Lupron for 6 months at the start
  • The off-cycle was stopped when PSA increased to 2.5 ng/ml
  • The on-cycle was stopped when PSA fell to 1.0 ng/ml
  • Castration resistance was declared if there were 3 consecutive PSA increases above 4.0 ng/ml during the on-cycle.

The trial was stopped 36 months after randomization. In that time:

  • Only 11% became castration-resistant
  • There was no difference in castration resistance between iADT and cADT
  • Testosterone only rose to about half of the baseline level during the off-cycle
  • Overall survival was high (85%), and there was no significant difference between groups
  • There were no differences in side effects or quality of life between iADT and cADT

While the trial didn't run long enough for meaningful differences to emerge, the lack of a quality-of-life benefit for iADT may dissuade men in this situation from attempting iADT. 

For newly detected patients with cancerous pelvic lymph nodes, a STAMPEDE trial has proved that continuous use of 3 years of ADT and 2 years of abiraterone improves survival and delays castration resistance over ADT alone. 

These patients can potentially be cured with whole pelvic radiation and intensive hormone therapy. Such potentially curative treatment has been suggested by retrospective studies. Prospective randomized clinical trials  (like this one and this one)will determine whether radiation with adjuvant hormonal therapy can provide a curative option to patients who are newly diagnosed with cancerous pelvic lymph nodes.

5. Metastatic Hormone Sensitive PCa (mHSPC)

Maha Hussain et al. reported the results of the SWOG-S9346 RCT. They randomized 1,535 men who were sensitive to hormone therapy.

  • Half were randomly assigned to cADT, half to iADT
  • Half were recurrent after primary prostatectomy or radiation; half had not been treated previously
  • All responded to 7 months of ADT with a PSA<4 ng/ml
  • In the iADT cohort, vacation was ended when PSA hit 20 ng/ml (10 ng/ml at doctor's discretion), and was triggered when PSA fell to 4 ng/ml. They were taken off the study if PSA didn't fall to 4 ng/ml while on ADT, or if PSA rose again before the first 3 months of starting a vacation.
  • Half had extensive metastases (ribs, long bones, viscera); half had minimal metastases (axial skeleton and lymph nodes).
  • Median PSA at baseline was 41 ng/ml

After a median follow-up of 10 years:

  • Overall survival was 5.8 years for cADT vs. 5.1 years for iADT
  • Mortality increased 10% due to iADT (range 23% increase to a 1% decrease with 90% confidence). 
  • Because the median increase did not reach the prespecified 20% hazard ratio for a clinically important difference, but the confidence interval included it, and a small percent (1%) lived longer with iADT, the study was considered statistically inconclusive. In other words, iADT may have been inferior, although they couldn't prove it definitively with the statistics obtained.
  • The iADT cohort had better erectile function and better mental health at 3 months but not thereafter.
  • There was no difference in adverse events.
  • Castration-resistance started after the same amount of time in each group, after adjustment for allowing the iADT group to prove rising PSA while receiving treatment (Figure S5).
A secondary analysis of SWOG-S9346 trial combined with Medicare codes focused on the long-term side effects of iADT vs cADT. After 10 years:
  • Thrombotic and ischemic events (e.g., heart, lung, or brain blockages and strokes) were significantly worse for iADT (33%) than for cADT (24%)
  • There were no significant differences in bone, endocrine, or cognitive events.

6. Metastatic Castration-Resistant PCa (mCRPC)

One of the causes of castration resistance is that the androgen receptor (AR) amplifies (upregulates) in each cancer cell. Because there are now so many copies of the AR, it takes very little androgen to activate cell replication. Some patients suppose that once they are castration-resistant they can cease using ADT. The opposite is true. They are more sensitive than ever to even the slightest amount of testosterone.

While iADT cannot be used, some researchers at Johns Hopkins hypothesized that rapid alteration between high testosterone and very low testosterone, called Bipolar Androgen Therapy, or BAT, may be able to retard AR upregulation.  In clinical trials so far, BAT seems to slow enzalutamide resistance in some men (20%-30%) but accelerates progression in others (see this link). There has been some progress: those men with high AR activity seem to benefit. The test is so far only available at Johns Hopkins. There are already concerns about safety, so patients should not attempt BAT outside of a carefully monitored clinical trial.

II. No Difference in Time to Castration Resistance

The original hope of iADT was that it would slow progression to castration resistance. This was based on tests in mice conducted by Bruchovsky. In clinical trials, this early hope did not pan out. All of the randomized clinical trials with homogeneous patient populations: SWOG-S9346NCIC-CTG PR.7ICELAND, and EC507 confirmed that the time to castration resistance was not different for iADT and cADT. Any reduction of evolutionary selection pressure with iADT is balanced by the reduction in sheer numbers with sustained cADT. This is not surprising, given that intensive hormonal treatment with ADT and Zytiga, Xtandi, or Erleada has been proven to delay castration resistance in men who are mHSPC. 

III. Testosterone Recovery with iADT

The only reason to take a vacation from ADT is if testosterone recovers enough to provide relief from symptoms. Nabid et al. reported the testosterone recovery to normal testosterone based on how long they received ADT and whether their testosterone level was normal or below normal at baseline. Their data is from men curatively treated with ADT and radiation for intermediate and high-risk PCa. This table summarizes their findings:

Percent who recover to normal

ADT Duration

Years to recover to normal T

among patients normal at baseline

among patients below normal at baseline

6 months

1.5 yrs



18 months

3.1 yrs



36 months

5.0 yrs



For 82% of men who have normal testosterone (T) at baseline and start with 6 months of ADT, it will take 1.5 years of vacation for their T to recover to normal levels. And almost half of men with below normal T at baseline will never obtain normal T levels. Older age and diabetes decrease the odds of T recovery.

A man who desires an ADT vacation should consider whether the vacation is likely to last long enough to give him a sufficient break from symptoms. Because men will be starting their vacation from castration at baseline, most men will never get the desired break.

Ong et al. similarly reported on testosterone recovery based on several clinical trials. A third of the men never enjoyed recovery to normal testosterone (>300 ng/dl or > 10.5 nmol/L). Older men (>65) were 20-33% less likely to recover normal testosterone.

Time (median) to recovery to normal T (300 ng/dl)

ADT Duration

Percent who recover to normal T

among patients average at baseline

among patients normal at baseline

3 months

} 67%

6.2 months

5.5 months

6 months

15.2 months

12.7 months

18 months

36.0 months

30.8 months

Dai et al. reported the time it took to recover to normal level (>250 ng/dl) of T after one treatment with 9 months of ADT. T at baseline determined T recovery time.

T Recovery (> 250 ng/dl) Time 

Percent who recover to normal

1 month


3 months


6 months


9 months


12 months


Tunn et al. reported specifically on men on iADT. They found that after 6 months of ADT, T recovery to baseline occurred in 79% in the first vacation, taking a median of 100 days. Recovery diminished in the second vacation - 65% recovered in 115 days. They also found no difference in time to castration resistance between iADT and cADT.

Relogulix (Orgovyx) is a fast-acting oral medication that provides ADT. It is a better choice for iADT. After taking it or Lupron for almost a year, T rose to normal levels within 3 months with Orgovyx but barely above castration level with Lupron (see this link).

IV. Earlier Use of iADT

It has been hypothesized that iADT is more beneficial if used earlier. PET scans may be able to identify occult metastases while they are still small enough for occasional hormone therapy to keep them in check. PRESTO and similar trials of short-term intensive use of second-line hormone therapies may be able to provide a longer and safer break from side effects.

V. iADT Protocols

There are no established iADT protocols. It is always based on judgment, and should be arrived at after discussion with one's oncologist. Here are a few factors to consider.

1. PSA after first ADT cycle

An undetectable (<0.2 ng/ml) PSA nadir, whether achieved rapidly or slowly, on the first cycle of ADT is prognostic for successful cycles with iADT. If the lowest PSA is still detectable after several months of ADT, especially if a high nadir is achieved rapidly, cADT may be a better strategy (see this link).

2. Time on On-Cycle and Off-Cycle

  • The Pr.7 trial used an arbitrary protocol of 8 months both on- and off-cycle.
  •  Others continue the on-cycle for at least a year. 
  • The time off-cycle may be different from the duration of the on-cycle. 
  • One can use an arbitrary time for the on-cycle and use a different factor, say PSA doubling time, for the off-cycle. 
  • One can let the on-cycle duration be variable: say, 8 months for the first on-cycle, 12 months for the second, 18 months for the third.
  • The on-cycle duration variability can be based on the previous on-cycle PSA history (e.g., increasing nadirs), or off-cycle factors (e.g., higher PSA in last off-cycle).

3. Testosterone level achieved on the Off-Cycle

Since there is no other known purpose of iADT than to maintain quality of life, it may make sense to continue the off-cycle until normal testosterone (T) is maintained for some length of time. Some men will never achieve normal T levels (see above), so there is no point in risking iADT. It is important to measure T at baseline and during the off-cycle.

4. Maximum PSA target on Off-Cycle

The SWOG trial of men with metastases visible on a bone scan/CT used a maximum PSA of 20 ng/ml (10 ng/ml at doctor's discretion) as the signal that it was time to end the vacation. Trials that look at non-metastatic patient groups usually use a much lower PSA threshold for ending the vacation (typically 4 ng/ml). PET scans can detect metastases at lower PSAs (see this link), so the threshold may be set somewhere in between. The patient can decide what threshold he is comfortable with.

5. PSA Doubling Time (PSADT)

It is reasonable to use rapid PSA doubling time (PSADT) as the signal that it is time to end the ADT vacation. Typical threshold PSADTs may be 3, 6, or 9 months, depending on the patient's degree of comfort. Here is a PSADT calculator.

6. Symptoms/Radiographic Progression

PSA will usually provide an early signal of progression. However, the appearance of new metastases, enlarged metastases, bone pain may provide evidence of progression even before PSA has picked it up. The Bone Scan Index may be a useful metric. 

7. Finasteride on Off-Cycle

Retrospective analysis suggested that finasteride might be helpful in extending the vacation time (see this link). However, when it was tried in the prospective clinical AVIAS trial, there was no benefit in extending the off cycle by adding dutasteride.

8. Biology/Genomics

We are learning how to use genomic tools as an aid to decision-making. Recurrent, non-metastatic men with a high risk of developing metastases (Decipher high-risk) may wish to think twice about iADT, while those with low-risk Decipher scores may feel more comfortable opting for iADT. A recent new test developed by Veracyte (the company that makes Decipher) may one day be able to identify patients who are very responsive to hormone therapy and may be able to try iADT. Johns Hopkins has developed a test of Androgen Receptor activity that may prove useful in determining whether iADT with BAT makes sense.

9. Metastasis Directed Therapy (MDT) using SBRT

Men who play "whack-a-mole" with metastases as they crop up usually see their PSA drop. This is because serum PSA comes mostly from larger, detectable metastases that have developed their own blood supply. It is tempting to use iADT when serum PSA is negligible; however it may be risky to take long ADT vacations when PSA has been artificially tampered with. See "The Perils and Pitfalls of Treating PSA."

Tang et al. conducted the EXTEND trial at MD Anderson to see if SBRT to oligometastases could extend the ADT vacation without risk. 87 oligometastatic men were randomized to get ADT with or without SBRT. After 6 months, all were given a vacation from ADT. The vacation ended when PSA reached 20 or new metastases appeared. Those who got SBRT were able to take a significantly longer vacation before progression.

10. Adaptive iADT

Several schemes have been proposed for determining the optimal way of using iADT. The goal of these mathematical models is to delay castration resistance. They make adjustments to ADT use based on each person's response, and change as his tumors evolve. They can be thought of as tailoring ADT to suit the individual. So far, they have only been used clinically in small pilot trials or proposed pre-clinically. Here are a few examples:

A Phase 1b Adaptive Androgen Deprivation Therapy Trial in Metastatic Castration Sensitive Prostate Cancer

Evolution-based mathematical models significantly prolong response to abiraterone in metastatic castrate-resistant prostate cancer and identify strategies to further improve outcomes

Integrating evolutionary dynamics into treatment of metastatic castrate-resistant prostate cancer

Practically scheduling hormone therapy for prostate cancer using a mathematical model

Intermittent Androgen Suppression: Estimating Parameters for Individual Patients Based on Initial PSA Data in Response to Androgen Deprivation Therapy

VI. Cardiovascular (CV) Adverse Events (MACE)

The most life-threatening adverse events that can be attributed to ADT are cardiovascular: MACE=Major Cardiovascular Event (myocardial infarction or stroke).

In the SWOG-S9346 trial by Hussain et al., thrombotic and ischemic events (e.g., heart, lung, or brain blockages and strokes) were significantly worse for iADT (33%) than for cADT (24%). CV events are highest during the first 6 months of initiating ADT. It may be that the fluctuating T and estrogen levels inherent in iADT causes coagulation. Oral estrogen, which results in peaks and valleys in serum concentration, was known to cause blood clots and was eliminated as a therapy for that reason.

However, a meta-analysis of iADT trials found no difference in CV events compared to cADT, but there was a difference in deaths due to CV events. Those who used iADT were 15% more likely to die of MACE.

Orgovyx has been found to have a better CV risk profile than Lupron, although MACE incidence is not high for either drug. Incidence of MACE was 2.9% for Orgovyx vs. 6.2% for Lupron (see this link). If MACE occurred, it usually occurred within 6 months of starting ADT, and was significantly higher in men with a history of it (3.6% for Orgovyx vs. 17.8% for Lupron). GnRH antagonists (like Orgovyx or Firmagon) may release proteins that prevent plaques from forming in cardiac blood vessels (see this link), while GnRH agonists (like Lupron) may increase plaque instability (see this link and this link). The PRONOUNCE trial, which would have been definitive, failed to adequately recruit, and was ended early with no difference in MACE at 1 year between Firmagon and Lupron. A retrospective study suggested that Firmagon had lower MACE than Lupron.

VII. Managing Other ADT Side Effects

It may be possible to at least manage some of the most annoying ADT side effects without resorting to iADT. Here are interventions that can be used now or on the horizon for some of the common side effects of ADT. Each patient must determine for himself the balance between interventions and risk of the side effects.

1. Fatigue

The small randomized EXTEND trial at Duke last year reported that men who undertook a supervised program of aerobics and weight training before and during hormone therapy were able to significantly improve their fatigue scores and quality of life relative to men who did not take the program. Similar programs have been found to combat fatigue in small randomized trials in Australia (see this link and this one), and the UK

There is a Phase 3 trial of Exercise and Methylphenidate (Ritalin) at MD Anderson with results expected by Nov. 2023.

Stopping smoking and restricting alcohol use may be beneficial.

Weight-bearing exercise may be contraindicated in men with multiple bone metastases due to risk of fracture. Cardiovascular morbidity may preclude aerobic exercise in some men. One should always check with one's doctors before beginning an exercise regime.

2. Libido

It should be understood the loss of desire for sex (libido) is not necessarily accompanied by a loss of erectile function, Men are often still able to have functional erections while on ADT if they use Trimix. Many men and their partners learn to value intimacy without intercourse. In some men, the loss of libido leads to a deterioration of relationships and a loss of one's masculine self-concept causing psycho-social problems.

3. Bone Loss

Long-term use of ADT leads to loss of bone mineral density (BMD). Resistance exercise and estrogen patches (see this link) can help maintain BMD.  Unless there is fracture risk from multiple metastases, bone restorative agents (Zometa or Xgeva) should not be used before castration resistance because their most serious side effects are cumulative. 

Excess calcium intake should be avoided due to risk of hastening progression (see this link and this one), cardiovascular side effects and kidney stones. There is no evidence that Vitamin D has any benefit unless one has a deficiency (see this link); in fact, high exogenous doses can pull calcium out of bones. Bloodwork at baseline and annually can determine if there is a deficiency.

Men using ADT should have a DXA scan at baseline, and annually thereafter. Here is a link for calculating FRAX score.

4. Lean Body Mass/ Muscle strength

Exercise has been found to help maintain lean body mass and avoid fat accumulation in a large number of small randomized trials (see this link), including this one. Transdermal estrogen is also known to preserve lean body mass. Amgen was developing a drug that may one day be used to inhibit myostatin in men on ADT (see this link and this one).

5. Metabolic Syndrome/Hyperlipidemia

Body Mass Index (BMI) and metabolic syndrome increases are well-known effects of ADT. They have been found to worsen prognosis. Again, exercise can help ameliorate it.

6. Hyperglycemia/ Insulin Resistance

Pioglitazone (Actos) an FDA-approved insulin sensitizer is being investigated as an adjunct to ADT in this clinical trial.

7. Hot Flashes

The following are good, albeit imperfect, solutions for hot flashes: aural acupuncture, estrogen patches, Progesterones (Megace or Provera), venlafaxine (Effexor), and oxybutynin.

8. Mental Effects/Mood Swings/Depression

Mindfulness, psychotherapy and antidepressants may help. Vortioxetine (Brintellix), an antidepressant, has been used in a pre-clinical study to reverse the ADT-induced cognitive impairment in rats.

9. Anemia

ADT may cause anemia in some men due to the lack of erythrocyte stimulation that testosterone would normally accomplish (see this link).  Erythropoietin (Procrit) may be able to reverse it if red blood cell levels get seriously low.

VIII. Shared Decision-Making

If you are feeling lost and confused after reading all of the above considerations about iADT, you are not alone. This is a consequential decision that should not be made lightly. It is a good idea to have a detailed conversation with your oncologist and significant support network.

Saturday, February 18, 2023

Duration of ADT needed with salvage radiation

No one wants androgen deprivation therapy (ADT) along with ("adjuvant to") salvage radiation therapy (SRT). We are accumulating evidence about how long one needs to stay on it to prevent the cancer from coming back, but judgment is still necessary.

There are some situations where it is unclear that SRT is needed at all (discussed in this link). This includes: a very long time (>18 months) before biochemical recurrence (BCR), slow doubling time, low Gleason score, elderly, significant comorbidities, no metastases with PSMA PET, and low Decipher score.

0-6 months ADT beneficial

GETUG-16 (article here) found that 6 months of ADT is better than no ADT. Incidence of metastases was improved by 27% among 743 patients.

SPPORT (RTOG 0534) found that 4-6 months was beneficial for everyone and that there was no difference between 4 and 6 months.  It was a very large trial (n=1,762) and used 8-year Freedom from Progression (mostly PSA) as its primary endpoint.

RADICALS-HD found that 6 months was no more beneficial than none! This was a large trial (n=1,500) that ran for 15 years. It used Metastasis Free Survival (MFS) as its primary endpoint. There was an 11% improvement in incidence of metastases which was not statistically significant.

DADSPORT meta-analysis sought to resolve the conflicting findings by combining the results of all 3 trials. It found an 18% improvement in incidence of metastases.

The endpoint and the follow-up are important. For men who are aged 60-70 at the time of prostatectomy, none of the trials had long enough follow-up to detect a difference in overall survival. MFS improvement may be small in the short-run, but metastases may appear later and adversely affect quality of life. Those who want to be definitively cured (i.e., no evidence of disease as evinced by PSA) should have at least short-term ADT.

24 months of ADT beneficial

RTOG 9601 showed that 24 months of adjuvant ADT did not improve survival when postprostatectomy PSA was below 0.7 ng/ml. A recent analysis by Spratt et al. suggested that adjuvant ADT is always necessary when PSA ≥ 1.5 ng/ml, but that risks may outweigh benefits when PSA is lower than 0.6 ng/ml. There were 760 patients with 13 years of follow-up. The primary endpoint was overall survival.

RADICALS-HD showed that 24 months of ADT improved survival over none or 6 months. 10-year MFS improved from 72% to 78%, while incidence of metastases declined by 23%. In the subgroup that had a PSA>0.5, incidence of metastases declined by 33%.

8 months (36 weeks) of ADT with enzalutamide

The EMBARK trial found that by intensifying ADT with enzalutamide (Xtandi) compared to ADT alone, the MFS improved by 58%, and PSA-free survival improved by 97% with 61 months of follow-up.

6 months of ADT with apalutamide and abiraterone

The Formula 509 trial found that by intensifying ADT with both apalutamide (Erleada) and abiraterone (Zytiga) compared to bicalutamide 50 mg/day, MFS improved by 43%, and PSA-free survival improved by 29% with 34 months of follow-up. Among post-op patients with PSA>0.5, MFS improved by 68%.

Positive lymph nodes

When cancerous lymph nodes are detected via pelvic lymph node dissection (PLND) at the time of prostatectomy, there is little doubt that 2-3 years of ADT are needed along with whole pelvic SRT (see this link). A PSMA PET scan may also identify cancerous pelvic nodes. One of the STAMPEDE trials lends credence to this strategy. They found that in men who were newly diagnosed with positive lymph nodes on a CT scan, 3 years of ADT with 2 years of abiraterone, decreased incidence of distant metastases by 47%. While this wasn't post-prostatectomy, it is hard to see why that fact would make a difference.

An NRG Oncology clinical trial is randomizing node-positive recurrent patients who will be getting SRT to 2 years of ADT with or without apalutamide.

AI and Genomics

Artificial intelligence (AI) is proving useful in determining the optimal duration of ADT. AI depends on feeding a lot of data about patients and their outcomes, so it will improve as a tool over the years.

Decipher scores based on the genomics of prostatectomy tissue can help discriminate between those that need more hormone therapy and those that need none.

Similarity to Adjuvant ADT with Primary Radiation

There is no reason why the decision about duration of adjuvant ADT post-prostatectomy should be different from the duration with primary external beam therapy. In general, the higher the risk, the longer the optimal duration. There are no precise cut-offs, so judgment and discussion with your radiation oncology is necessary.