Sunday, July 9, 2017

How soon after surgery should salvage radiation begin?

Patients and their doctors often have to make a critical decision soon after surgery – at what point after surgery, if at all, should salvage radiation therapy be started? Immediate treatment is often too early, and waiting can be too late. Two new papers give us much-needed help in finding the “Goldilocks moment.”

 Let’s begin with a shared understanding of the definitions of some commonly used terms and abbreviations:
  • Adverse pathology means that the post-op pathology report indicates that cancer was found in one or more of the following places:
    • Outside of the prostate capsule (pathological stage T3a), or
    • In the seminal vesicles (pathological stage T3b), or
    • Locally, but at a distance from the prostate (pathological stage T4), or
    • At the surgical margin, where the surgeon has cut through the cancer — a “positive surgical margin” (PSM).
  • Adjuvant radiation therapy (aRT) means radiation given after prostatectomy when there is adverse pathology, but before the PSA becomes detectable.
  • Salvage radiation therapy (sRT) means radiation given after prostatectomy but also only after a biochemical recurrence (BCR).
  • Early salvage radiation therapy (early sRT) means radiation given after the point that aRT would be given, but before sRT would be given.
  • Wait-and-see is the strategy of waiting until after a BCR to decide what to do. The wait-and-see decision may be sRT at any time after BCR, or the patient may decide to forgo radiation, use hormone therapy, or do nothing until there is evidence of clinical progression.
  • Biochemical recurrence (BCR) post-surgery is now defined as a confirmed PSA ≥ 0.2 ng/ml. This was chosen in 2007 because it was the most frequently used threshold in published studies. When those studies began, a PSA of 0.1 ng/ml was as low as could reliably be measured. Anything below that was undetectable at the time, and 0.2 ng/ml was arbitrarily deemed a biochemical recurrence.
  • An ultrasensitive PSA (uPSA) test is any PSA test that can reliably detect PSAs below 0.1 ng/ml. While the definition of biochemical recurrence has not been changed, detectable levels of PSA are now as low as 0.001 ng/ml on some commercially available ultrasensitive tests.
The above definitions can be illustrated as potential decision points along a line showing uPSA values after prostatectomy and adverse pathology:

Why start sooner than sRT/wait-and-see, but later than aRT?

Three major randomized clinical trials have shown that there is an oncological advantage to aRT over a wait-and-see strategy in patients with adverse pathology after prostatectomy. This is hardly surprising, especially because “wait-and-see” includes patients who never even received salvage radiation, or may have only received palliative hormone therapy. There has never yet been a randomized clinical trial comparing aRT to sRT.
Based on those studies, both the American Urological Association (AUA) and the American Society of Radiation Oncologists (ASTRO) endorse aRT in their guidelines. However, in spite of those guidelines, only 43 percent of men who get radiation after prostatectomy do so within the first 6 months of their surgery (see Sheets et al.). Why aren’t more patients choosing aRT?
Patients (and many doctors too) worry about over-treatment, and the adverse effects of radiation on recently cut tissues. Immediate aRT may represent over-treatment for many men for whom small, detectable amounts of PSA are leaked into the serum from benign tissue left behind by surgery, or men in whom any tiny amounts of malignant tissue left behind may be indolent or susceptible to scavenging by the immune system. Kang et al.found that, among men with capsular perforation, PSMs, or seminal vesicle invasion after surgery, only 17 percent actually went on to have a true biochemical recurrence. The other advantage to waiting is that it may allow for better recovery of continence and erectile function after surgery in at least some patients.
All three of those above-mentioned clinical trials accrued participants before uPSA tests became routinely available. Although the use of uPSA testing is controversial, its widespread use has led many patients and clinicians to wonder whether waiting for some low PSA value – “early salvage radiation” – might be equivalent in outcomes to aRT.
There are randomized clinical trials underway in Canada and the UK, in Australia and New Zealand, and in France to determine whether early sRT might be equivalent to aRT in terms of survival. The combined results of those trials may have sufficient power to answer the question. Those findings will be definitive, but in the meantime two groups of researchers have retrospectively analyzed their patient outcomes for clues.

Ultrasensitive PSA reliably predicts eventual biochemical recurrence (a UCLA study)

Researchers at the University of California, Los Angeles (UCLA) looked at available evidence that the uPSA test might afford radiation oncologists the opportunity to treat patients late enough that they are assured to be on a path to clinical recurrence, yet early enough that waiting for treatment does no oncological harm. Kang et al. conducted a retrospective analysis of data from 247 patients treated at UCLA between 1991 and 2013 who were found on post-op pathology to have adverse disease characteristics — stage pT3-4 disease and/or positive surgical margins — and who received uPSA tests. That cohort had the following characteristics:
  • Positive margins in 79 percent of patients
  • Patients were excluded if
    • They had already received radiation and/or hormone therapy, or
    • They were found to be node-positive at the time of surgery
  • Pathological stage T3/T4 in 55 percent of patients
  • Gleason score ≥ 7 in 81 percent of patients
  • Initial, pre-surgical PSA ≥ 10 in 29 percent of patients
  • Time to first post-op PSA, 3 months
  • Median number of PSAs post-surgery and before subsequent treatment, 4
  • Median follow-up, 44 months
Kang et al. found that a uPSA ≥ 0.03 ng/ml was the optimal threshold value for predicting biochemical recurrence (BCR). Other findings included:
  • uPSA ≥ 0.03 ng/ml was the most important and reliable predictor of BCR. It predicted all relapses (no false negatives: no one was under-treated), and hardly ever predicted relapses incorrectly. Only 2 percent would be over-treated by waiting for this cut-off.
  • It was especially prognostic if found on the first uPSA test after surgery.
  • Even if the first uPSA test was undetectable, any subsequent test where uPSA ≥ 0.03 ng/ml predicted BCR.
  • Other lesser predictors of recurrence were pathologic Gleason grade, pathologic T stage, initial PSA before surgery, and surgical margin status.
  • At 5 years of follow-up, 46 percent of patients had a BCR using the “standard” PSA ≥ 0.2 definition, 76 percent using the PSA ≥ 0.03 definition.
  • Treating when an ultrasensitive PSA level reached 0.03 ng/ml gave a median lead time advantage of 18 months over waiting until PSA reached 0.2 ng/ml.
  • It was necessary to monitor PSA for at least 5 years post-op, and to test at least every 6 months.
What is not known at this time is whether there is a survival disadvantage from waiting until uPSA reaches 0.03 ng/ml if it is not at that level immediately after surgery. (update 10/2018)  Kang et al. report that there is indeed a survival advantage from treating if the first uPSA level (at 3 months after surgery) reaches 0.03 ng/ml. So the lead-time advantage actually translates to a survival advantage for men with adverse pathology who have a persistent uPSA of at least 0.03 ng/ml.
If the findings of this study by Kang et al. are confirmed by randomized clinical trials, there is certainly a strong argument that all patients with adverse post-op characteristics should be monitored routinely using ultrasensitive PSA tests, and offered treatment with salvage radiation when their PSA level reaches 0.03 ng/ml. It is also arguable that the definition of biochemical recurrence after prostatectomy should then be changed to 0.03 ng/ml, which would be more practical.

Ultrasensitive PSA can reliably predict eventual biochemical recurrence at 2 months after surgery (a Czech study)

A Czech study (Vesely et al. and updated here) looked at a group of 116 patients (205 updated) who had PSMs after surgery. Unlike the UCLA study, staging was not a selection criterion. The two studies’ goals were somewhat different. While the UCLA study didn’t start uPSA testing until 3 months after prostatectomy, in this study uPSA testing was begun at 2 weeks post-surgery. Most urologists wait for 3 months because surgery sheds a lot of PSA into the serum, and it takes a while for that excess to clear out. The goal in this study was to find out just how early in time after prostatectomy they could detect a uPSA prognostic for BCR, whereas the UCLA study sought to find out how late in uPSA progression they could detect a PSA prognostic for progression. The Czech cohort had the following characteristics:
  • Only patients with PSMs were included
  • Patients who received aRT or hormone therapy were excluded
  • Pathological stage T3/T4 in 54 percent of patients
  • Gleason score ≥ 7 in 51 percent of patients
  • Initial, pre-surgical PSA ≥ 9.2 in 50 percent of patients
  • Time to first post-op PSA, 14 days
All patients’ PSA levels were measured on days 14, 30, 60, 90, and 180 post-surgery, and at 3-month intervals thereafter; the median follow-up was 31 months.
Vesely et al. found that the uPSA on day 30 had predictive accuracy of 74 percent for recurrence, and reached a maximum of 84 percent by day 60, when the uPSA was 0.04 ng/ml (increases in accuracy afterwards were not statistically significant). The following table summarizes their findings:

  • Applying the uPSA cut-off at day 60 as the indicator for sRT would result in the decrease of over-treatment from 53 to 4 percent. Of the 33 percent who would be under-treated, 86 percent would eventually be discovered at subsequent follow-up at 3 months, and 98 percent by 4 years.
  • uPSA at day 14 was not prognostic for recurrence.
  • The following were not predictors of recurrence in men with PSMs: pathologic Gleason grade, pathologic T stage, initial PSA before surgery.
  • Neither the location nor the extent of PSMs had any significant impact on the frequency of BCR.
  • At 5 years of follow-up, 47 percent of patients had a BCR using the “standard” PSA ≥ 0.2 definition.
The main conclusion of this study is that uPSA tracking can begin earlier. Even as early as 30 days post-op, uPSA has good accuracy for predicting BCR in men with PSMs, and at 60 days, the accuracy is even better. If duplicated in larger studies, this implies that uPSA testing ought to begin 1 or 2 months earlier than it usually does at present.
The predictive accuracy of this study is somewhat lower than the UCLA study, perhaps in part because the sample size was half as big. The results in terms of uPSA prognostic threshold values, however, are surprisingly similar. Here, the threshold was 0.04, 0.01, and 0.02 ng/ml at 2, 3, and 6 months, respectively. In the UCLA study, the threshold was 0.03 ng/ml at any time from 3 months onward. Because the uPSA ≥ 0.03 at 90 days and onwards was 100 percent predictive of BCR in the UCLA study, and led to almost no under-treatment, it may well obviate the need for earlier uPSA testing advocated in the Vesely et al. study.
As in the UCLA study, however, it is not yet known whether early sRT translates to a survival advantage over waiting for BCR.
For the first time, these studies give the patient and doctor new insight into the timing and use of uPSA to predict BCR. If confirmed, setting a uPSA threshold at about 0.03 ng/ml would reduce over-treatment compared to aRT, and would reduce under-treatment compared to sRT. We await the completion of three randomized clinical trials before we have more reliable data.
written 1/4/2015

Thursday, July 6, 2017

First US randomized clinical trial of oligometastasis-directed SBRT

In a recent commentary (see this link), we saw that some clinicians are making unsubstantiated claims of cancer control from treatment of oligometastases (less than 5 detected metastases). Only a randomized clinical trial (RCT) can prove that there is any benefit to such treatment. Johns Hopkins has announced the first such RCT in the US.

Stereotactic body radiation therapy (SBRT) is the treatment of choice because it is precise, as well as convenient for the patient (usually completed in 1-5 treatments). It is important to distinguish between two different situations that may involve oligometastases:
  1. Metastasis-directed SBRT after primary treatment (prostatectomy or prostate radiation) and any local salvage radiation has failed. This is sometimes called "metachronous" treatment of recurrent prostate cancer.
  2. Radiation to the prostate and oligometastases in newly-diagnosed men, or men who are radiation- or surgery-naive but have progressed to castration-resistance.
  3. Radiation to metastases for the purposes of pain palliation, or to prevent fractures or spinal compression.
In addition, the situation may be different depending on whether the oligometastases are in the visceral organs, bones, extra-pelvic lymph nodes, pelvic lymph nodes, or some combination of these.

Phuoc Tran is the lead investigator of the "ORIOLE" RCT (NCT0268058) at Johns Hopkins described at this link. It is a small, Phase 2 trial for men in situation A described above. It has some noteworthy characteristics:
  • 36 men will receive SBRT, 18 men will receive standard-of-care treatment
  • Oligometastases are diagnosed by bone scan and CT
  • Patients will be balanced based on whether initial treatment was surgery or radiation, whether they've had hormone therapy, and whether the PSA doubling time was less than 6 months.
  • The primary outcome will be radiographic or PSA progression (by >25% over nadir and by > 2 ng/ml) after 6 months.
  • To be deemed successful, the treatment will have to reduce this measure of progression by 50%
There are several interesting secondary objectives of this RCT:
  • identification of additional metastases using the DCFPyL PET/CT
  • toxicity of treatment reported by doctors
  • pain palliation reported by patients
  • local control of metastases (see below)
  • Number of circulating tumor cells (CTC)
  • Genomic analysis of CTCs
  • Immune (T cell) response to treatment
  • Time until patients have to start life-long hormone therapy
We will see if the radiation activates a systemic T-cell response that may destroy cancer cells beyond the treated tumors (the abscopal effect).

It may seem odd that detection of fewer than 5 metastases by the DCFPyL PET/CT (developed at Johns Hopkins and now in expanded trials) is not a qualifying criterion. Perhaps they will change that for the Phase 3 trial. Or perhaps they want to prove the concept with a bone scan/CT because it will be several years before that PET scan (so far, the most accurate) is widely available and covered by insurance or Medicare. If it works for bone scan/CT-detected oligometastases, it will certainly work for DCFPyL PET-detected metastases.

Update (August 2017): Dr. Tran has made the following change in protocol:
We did change the criteria recently to allow men who had detectable disease on DCFPyL to enroll on the trial, BUT only if the DCFPyL did not show anything more than what is visible on conventional CT-AP and bone scan.  Our thought was that this would allow some patients of the "future" if you will (as PSMA-targeted imaging will be the SOC in 3-5 years) to be included on the trial, but because we do not allow men on the trial with DCFPyL scans that show us more than what is on conventional , we feel that still holds to original concept. 

It is also important to note what is not an objective of this early clinical trial. The outcome we most want to know is whether SBRT treatment of metastases extends overall survival. This 6-month trial will not tell us that. There is no doubt that local control will be excellent, but stopping the progression of 1-3 metastases does not necessarily mean that the cancer has been slowed down systemically at all. Certainly, PSA will fall as an immediate result of treatment. For those who are used to monitoring PSA as a measure of their cancer's systemic progression, this can be confusing. It's worth taking a moment to recall what serum PSA comes from in detectably metastatic disease. PSA is a protein on the surface of prostate cancer cells (and healthy prostate cells too.) It doesn't leak out into the blood from prostate cancer unless a tumor forms with its own blood supply. Tumor blood supply tends to be leaky, and so PSA is detected in the blood serum. Larger tumors with more blood supply put out more PSA. So irradiating those tumors and shrinking them is likely to eliminate the PSA they put out. But what about the micrometastases that do not yet have appreciable blood vessels? If there are thousands of them, will it matter that serum PSA was reduced for 6 months? No one knows the answer to that question and this Phase 2 study will not provide the answer. I hope they will provide radiographic progression-free survival separate from PSA progression-free survival.

For the answers to our most important questions we will have to look forward to the outcomes of some of the other RCTs that have longer follow-up than 6 months.

  • The CORE RCT (active, no longer recruiting) at Royal Marsden Hospital in London will have 5 years of follow-up (completion in 2024), and will include freedom from widespread metastatic disease and overall survival among the outcomes looked at. 
  • The STOMP RCT at University Hospital in Ghent had 2 years of follow-up looked at time to lifelong hormone therapy as its primary outcome (reviewed here). 
  • The PCX IX RCT (among castration-resistant patients) at Jewish General Hospital in Montreal will have 5 years of follow-up (primary outcome in 2025) and has radiographic progression-free survival as its primary outcome. 
  • The French RCT (recruiting, study completion in 2022) will look at radiographic progression-free survival with follow-up up to 3 years. 
  • The FORCE RCT at the University of Michigan (primary completion in 2022) will compare systemic treatment with ADT and any of Taxotere, Zytiga or Xtandi (at the discretion of the treating physician) to similar systemic treatment plus metastasis-directed SBRT for men with mCRPC who have not yet had any of those advanced systemic therapies. They will evaluate progression-free survival after 18 months. "Progression" is defined as alive and at least a 20% increase (and at least 5 mm net increase) in the size of tumors or any new metastases. They will detect metastases via bone scan/CT, However, they will also test whether PSMA-based PET indicators are as useful in among men with mCRPC as it is in men with newly  recurrent disease.





Wednesday, June 21, 2017

Eighth randomized clinical trial of hypofractionated radiation therapy

We now have an eighth randomized clinical trial of hypofractionated radiation therapy. There are no surprises: it showed that oncological and toxicity outcomes were not significantly different between the two regimens. We last looked at it here. This trial is unusual because of the length of follow-up.

Arcangeli et al. report the 10-year outcomes of their study covering 168 high risk patients treated using 3D-CRT (not IMRT) at the Regina Elena Cancer Institute in Rome between 2003 and 2007. The details of the treatments were as follows:
  • Half (85 patients) received conventionally fractionated (Conv)  80 Gy in 40 fractions
  • Half (83 patients) received hypofractionated (Hypo) 62 Gy in 20 fractions
After a median of 9 years of follow-up:
  • 10-year freedom from biochemical failure was 72% for the Hypo group vs. 65% for the Conv group.(no statistically significant difference)
  • 10-year prostate cancer -specific survival was 95% for the Hypo group vs. 88% for the Conv group (no statistically significant difference)
  • 10-year overall survival was 75% for the Hypo group vs. 64% for the Conv group (no statistically significant difference)
  • Hypofractionation was a significant variable in determining prostate cancer-specific survival in multivariate analysis
  • There were no differences in late-term grade 2 or higher urinary or rectal toxicity between the 2 groups.

There are a couple of caveats. For those who insist on rigorous analysis, the Hypo group had worse oncological and toxicity outcomes on an intention-to-treat basis. It was only after the patients were analyzed according to the treatment they actually received that the lack of statistically significant difference became apparent. James Yu, in an accompanying editorial, points out that blood in urine was 16.5% for the Hypo group vs. 3.6% for the Conv group. This may be a caution that hypofractionation should not be attempted using 3D-CRT. In the US, where IMRT is widely available, this should not be an issue.

Here's the table summarizing all 8 randomized clinical trials:


Randomized Clinical Trial
Risk Groups
Fractionation
5-yr bPFS
Urinary toxicity
Grade 2+
Rectal toxicity
Grade 2+
Ref.
PROFIT
100% intermediate
60 Gy/20fx
78 Gy/39fx
85%
85%
22%
21%
8%
14%
1
Fox Chase
67% Intermediate, 33% high
70.2 Gy/26fx
76 Gy/38fx
77%
79%
22%
13%
18%
23%
2
CHHiP
73% intermediate, 15% low, 12% high
60 Gy/20fx
74 Gy/37fx
91%
88%
12%
9%
12%
14%
3
MD Anderson
71% intermediate, 28% low, 1% high
72 Gy/30fx
75.6 Gy/42fx
89%†
85%†
16%
17%
10%
5%
4
RTOG 0415
100% low risk
70 Gy/28fx
73.8 Gy/41fx
94%
92%
30%
23%
22%
14%
5
HYPRO
>70% high, <30% intermediate
64.6 Gy/19fx
78 Gy/39fx
81%
77%
41%
39%
22%
18%
6, 7
Cleveland Clinic
49% low, 51% intermediate
70 Gy/28fx
78 Gy/39fx
94%
88%
1%
2%
5%
12%
8
Regina Elena
100% high risk
62 Gy/20 fx
80 Gy/40 fx
72%*
65%*
21%
14%
NA
NA
9
*10-year figures for the Regina Elena trial
† 8-yr failure-free survival update for MD Anderson

Tuesday, June 6, 2017

Newly diagnosed, metastatic (M1), but still hormone sensitive - best options

(Frequently Updated)

In the US, only 3% of new patients are newly diagnosed with metastatic, hormone-sensitive prostate cancer (mHSPC). "Metastatic," for the purposes of this analysis only includes distant metastases (Stage M1), but not pelvic lymph node metastases (Stage N1). This group has been the subject of many major randomized clinical trials over the last few years. CHAARTED, in the US, randomized to early docetaxel + androgen deprivation therapy (ADT) compared to ADT alone. STAMPEDE, in the UK and Switzerland,  has published several studies: one on the use of Zometa and Celebrex, one on docetaxel,  one on abiraterone+prednisolone (I'll refer to this combination as Zytiga), and two on debulking the prostate with radiation (one from STAMPEDE and one from HORRAD). They also included men with locally advanced and recurrent prostate cancer, which we will address at another time (see this link). 

LATITUDE was a multinational clinical trial comparing Zytiga+ADT to ADT alone. TITAN was a multinational trial comparing apalutamide (Erleada) +ADT to ADT alone. ENZAMET was a multinational trial comparing enzalutamide (Xtandi) + ADT to early antiandrogens +ADT. ARCHES assessed the effect of enzalutamide on radiographic progression-free survival. TITAN and ENZAMET are discussed in more detail here.

We can look at hazard ratios for overall survival. A hazard ratio (HR) of, say, 0.60 means that the treatment reduced the number of deaths by 40% compared to the standard treatment. Unless it is otherwise noted, the HRs we talk about are all statistically significant with 95% confidence.

Early use of docetaxel

The hazard ratios found for all metastatic men were as follows:
CHAARTED: 0.61
STAMPEDE: 0.81
GETUG-15: 0.90 (not statistically significant)

The hazard ratios for men with high volume mets only were:
CHAARTED: 0.60
GETUG-15: 0.8 (not statistically significant)
STAMPEDE: 0.81 (not statistically significant)

The hazard ratio for men with low volume mets only were:
CHAARTED: 1.03 (not statistically significant)
STAMPEDE: 0.76 (not statistically significant)

GETUG-15 was a French randomized clinical trial. It has been criticized for including men with more advanced disease than CHAARTED. When STAMPEDE showed similar results to CHAARTED, GETUG-15 was largely ignored, and early use of docetaxel became the new standard of care. Some argued that the  results of STAMPEDE and CHAARTED suggest that docetaxel should be considered for among all metastatic men, but a CHAARTED update suggests a benefit only among those with high volume of metastases. However, a STAMPEDE update showed no difference in overall survival or failure-free survival between the two subgroups. The STAMPEDE authors point to their larger trial and that their analysis applies more to newly diagnosed men, whereas the CHAARTED groups had more previously treated men. They advocate early use of docetaxel regardless of metastatic burden. (High volume was defined as visceral metastases or 4 or more bone mets with at least one beyond the pelvis or vertebrae.)

One should resist the temptation to compare HRs across studies. Each study had different patient characteristics, and PSA screening policies differ markedly in those countries. In fact, a recent analysis of the STAMPEDE outcomes of men who were randomly assigned to either Zytiga or docetaxel found that there was no difference in survival between the two treatments (see this link).

Early use of Zytiga

The hazard ratios found for all metastatic men were as follows:
LATITUDE: 0.66
STAMPEDE: 0.61

An unplanned secondary analysis presented at ESMO 2018 and published in European Urology looked at high volume vs low volume, and found it worked equally well in both situations:

The hazard ratios for men with high volume mets only were:
STAMPEDE: 0.60

The hazard ratio for men with low volume mets only were:
STAMPEDE: 0.64

Early use of Zytiga+Docetaxel

Overall survival is not available yet, but radiographic progression-free survival increased by 2.5 years (from 2.0 to 4.5 yrs) with the addition of abiraterone to docetaxel. Time to castration resistance increased by 1.7 yrs (from 1.5 to 3.2 yrs). See discussion of early results of PEACE1.

Early use of Erleada

The hazard ratio for metastatic men was 0.67

Early use of Xtandi

The  hazard ratio for all metastatic men was 0.66

The hazard ratio for men with high volume mets only was 0.74 - not statistically significant

The hazard ratio for men with low volume mets only was 0.48 - statistically significant


Early use of Debulking

The hazard ratios found for all metastatic men were as follows:
STAMPEDE: 0.92  (not statistically significant)
HORRAD:  0.90 (not statistically significant)

The hazard ratios for men with high volume mets only were:
STAMPEDE: 1.07 (not statistically significant)

The hazard ratio for men with low volume mets only were:
STAMPEDE: 0.68 (statistically significant)

Early use of Zometa+Celebrex

The hazard ratios found for all metastatic men were as follows:
STAMPEDE: 0.78 (see this link)

Which is best? 

The no-brainer here is Zometa+Celebrex. As long as the patient doesn't have contraindications like heart disease or bad teeth, it is cheap, non-toxic, and reduced risk of death by 22% at the 43 month follow-up. Zometa is usually given along with ADT anyway, so it is hard to argue against including this combination along with Zytiga, Erleada or docetaxel. However, the use of Zometa when one is still hormone-sensitive is controversial. An argument can be made for putting it off until there is evidence of osteoporosis on a DEXA scan - the risk of the worst side effect- osteonecrosis of the jaw - increases with the amount of time taking it.

The hormonal therapies have differing modes of action, but without a randomized clinical trial, it's impossible to say that one extends life more than the others. Xtandi and Zytiga are being compared in an ongoing arm of STAMPEDE. Zytiga prevents the formation of androgens by the adrenal glands and via intra-tumoral synthesis. A recent study suggests that it stops formation of testosterone by the testicles as well. Xtandi and Erleada block the androgen receptor and prevents its translocation into the nucleus, where it can invigorate the cancer even without outside androgens. Erleada also prevents "upgrading" of the androgen receptor - a mode of castration resistance where multiple copies of the androgen receptor appear on the cancer cell, so it can be activated by even the slightest amount of androgen. However, it is unknown whether it slows down castration resistance in clinical practice - the cancer cell evolves many workarounds. A small trial found that combining Zytiga and Xtandi did not improve survival in the castration-resistant setting. 

Because neither docetaxel nor Zytiga showed a clear survival advantage when men were randomized to one or the other (Sydes et al.), the decision must be made based on other factors.

Both docetaxel and Zytiga increase toxicity over ADT alone. In the LATITUDE trial, physicians reported grade 3-5 (serious to death) events among 68% taking Zytiga vs 52% on ADT only. Higher rates of grade 3 hypertension and hyperkalemia were observed. In the STAMPEDE trial, physicians reported grade 3-5 events among 47% of those taking Zytiga vs. 33% of those taking ADT only. Higher rates of hypertension and liver enzyme elevation were observed. In the TITAN trial (Erleada), where almost two-thirds had high-volume metastases, Grade 3 (serious) and Grade 4 (life-threatening) toxicities were similar (41-42%) for those who got apalutamide or placebo. In the ENZAMET trial, serious side effects were experienced by 42% of those taking Xtandi vs 34% of those taking an early antiandrogen. The rate of serious side effects is remarkably similar.

In the docetaxel trials, STAMPEDE reported grade 3-5 events among 52% taking docetaxel vs 32% taking ADT only. Neutropenia, lethargy and GI disorders were especially elevated. CHAARTED reported grade 3-5 events among 30% taking docetaxel. Neutropenia, fatigue, gastrointestinal and allergic reactions were elevated.

One might expect that the increase in toxic events would have been worse with docetaxel, but while they were different in kind, the incidence of all events requiring medical attention was similar for both treatments. All medicines seem to have lower incidence of side effects when they are used earlier, while patients are healthier.

High volume/low volume of metastases

Planned subgroup analyses of both CHAARTED and STAMPEDE showed that certain different therapies may improve survival depending on the number of distant metastases found using a bone scan/CT. Remember that high volume was arbitrarily defined as visceral metastases or 4 or more bone mets with at least one beyond the pelvis or vertebrae; low volume is anything less than that (often referred to as oligometastatic).

For men who are diagnosed with a low volume of metastases (oligometastatic), debulking can add to survival. STAMPEDE recruited participants before the benefit of early Zytiga was known, so it is unknown how the two therapies might interact. It is reasonable to speculate that early Zytiga may be used to radio-sensitize the cancer to debulking with radiation. The role of metastasis-directed SBRT has yet to be proven, but may be considered when safe to do so.

In a post-hoc analysis of LATITUDE data, men with high volume disease benefited from early use of Zytiga, but men with low volume disease did not. In STAMPEDE, there was no difference - Zytiga was equally effective in both groups. Erleada also seems to be equally effective in both groups. However, LATITUDE had mostly high-volume disease men in its sample. For men with a high volume of metastases, docetaxel or Zytiga (but not debulking) may confer a survival benefit). Xtandi seems to benefit most those with low volume of metastases.


Can they be combined or sequenced?

The PEACE-1 trial showed that the combination of docetaxel and Zytiga improved outcomes significantly.

A major clinical trial, ACIS, found that the combination of Erleada and Zytiga increased radiographic progression-free survival in men who were already castration-resistant. That combination improved results (in the AASUR trial) when given as an adjuvant therapy along with prostate radiation to men with very high-risk localized prostate cancer, and will be testedamong high-risk patients with high Decipher scores in the PREDICT-RT trial. The combination is being tried along with salvage radiation in men who have failed prostatectomy in the INNOVATE trial. An ongoing clinical trial is investigating whether Erleada combined with Zytiga extends survival in the relapsed hormone-sensitive setting.

There is a hint that docetaxel may have some efficacy in keeping Zytiga working longer. The androgen receptor always eventually becomes resistant to the effect of Zytiga. Sometimes resistance is attributable to a change in the androgen receptor called "the AR-V7 splice variant." There was a very small (n=14) trial at JH where they were looking at the role of the AR-V7 splice variant in resistance to second-line hormonals (Zytiga or Xtandi). In a few guys (6 out of 14) who were AR-V7 positive after that hormone therapy, they became AR-V7 negative after docetaxel treatment. This is also an effect that they were hoping that supraphysiological doses of testosterone might sometimes create (see this link).

This may work both ways. Hormonal agents may even re-sensitize the cancer to docetaxel after it has become docetaxel-resistant (see this link). It may turn out that alternating the use of chemo and advanced hormonals (and testosterone!) is a good strategy.

For logistical reasons, it may be useful to start with six cycles of docetaxel, which would take 15 weeks. In this way, Zytiga, Erleada or Xtandi can begin 15 weeks later. If one starts with Zytiga, it may take three or more years before it stops working and docetaxel can be tried (Among metastatic men, failure-free survival was about 4 years in STAMPEDE, radiographic progression-free survival was 33 months in LATITUDE). It seems that one can receive more therapies in less time if a patient begins with docetaxel.

It is possible that concomitant early use of Zytiga and docetaxel may have a synergistic effect on the cancer, and in preventing the onset of Zytiga resistance. This is pure conjecture and would have to be proved in a clinical trial. The downside is the cumulative side effects.

The other possibility is starting with docetaxel only and following up with the combination of Zytiga +ADT. By holding off on ADT use, it might delay some of the selective evolutionary pressure that leads to early Zytiga resistance. It is unknown whether early docetaxel without ADT has similar efficacy to the combination. Again, this is a good hypothesis to be tested in a clinical trial.


Will Provenge, Xofigo and Jevtana also be more beneficial if used earlier?

Isn't earlier always better? Not necessarily (see this link). Cancer is a moving target, continually altering its genetic make-up. What works when cancer is in one state may not necessarily work when cancer is in another state. There can be unpredictable interactions. Early and prolonged use of bicalutamide, for example, may actually eventually increase the cancer growth rate; yet, with cancers that have become castration-resistant, adding bicalutamide may sometimes slow it down.

Although Provenge is more effective when the patient's disease is less progressed (see this link), it was not any more effective when used for mHSPC (see this link). Xofigo is in a clinical trial for mHSPC, and Jevtana is in trials for use before docetaxel.

What about nuclear medicines?

An exciting new field is the use of nuclear medicines (alpha-emitters like Xofigo, and beta-emitters like Lu-177-PSMA). Their use has historically been restricted to men with mCRPC. There is a clinical trial of Lu-177-PSMA for men who are castration-resistant but are not yet detectably metastatic (see this link). The hope is that they can seek out and destroy micrometastases that may be in systemic circulation.

What happens if they are used later?

Most of the advanced prostate cancer medicines were approved for men who were metastatic and castration-resistant (mCRPC). In that setting, docetaxel adds a median survival of 3 months (see this link), compared to a median of 17 additional months among men with high volume metastases in the CHAARTED trial. Zytiga adds 4 months to survival among men who are castration-resistant and have had chemo (see this link). Median (50%) survival has not been reached with the limited follow-up of the STAMPEDE trial, but we can look at 60% survival and  note that the curves are diverging, so the median survival improvement is at least this large. In STAMPEDE, early Zytiga increased median survival by at least 18 months; In LATITUDE, early Zytiga increased median survival by 16.8 months.

We might surmise that if used after metastatic diagnosis but before castration-resistance sets in, the survival improvement might be somewhere in between. However, long-term use of ADT drives changes in the androgen receptor that might shorten the time during which Zytiga is effective. Docetaxel, on the other hand, remains effective even after advanced hormonal agents have been utilized.

What are the other alternatives for metastatic hormone-sensitive prostate cancer (mHSPC)?

Supraphysiological doses of testosterone alternating with ADT (called Bipolar Androgen Therapy or BAT) has shown efficacy in some men (see this link). Expanded trials will tell us which men are most likely to benefit from it.

Treatment of the prostate even after metastases have been discovered  (called "debulking") is an intriguing prospect. However, the most recent reported arm of the STAMPEDE trial showed that prostate-only radiation only provided a survival benefit in oligometastatic men (see this link). There are clinical trials at MD Anderson and Rutgers (not recruiting), and registries at UT Southwestern and MSKCC and the Los Angeles VA that will further explore this opportunity. Princess Margaret Hospital in Toronto is using SBRT for this purpose (see this link). Other trials are ongoing in Europe (this one includes docetaxel and Zytiga): Ghent, and Hamburg.

Other early-use therapies are combined with ADT in clinical trials. These are no longer recruiting:
These are still recruiting: