Saturday, February 22, 2020

ProtecT Randomized Clinical Trial: Patient outcomes by treatment received - active monitoring, prostatectomy, or radiation

In an earlier article (see this link), we looked at the only trial that randomized men with localized prostate cancer to either "active monitoring" (AM), radical prostatectomy (RP), or external beam radiation (EBRT). AM was less restrictive than today's active surveillance protocols (it included men who were not low risk) and it did not include mpMRI or follow-up biopsies. EBRT was lower dose than contemporary guidelines, included short-term ADT for everyone, and used a more toxic technique (3D-CRT) than IMRT prevalent today. RP was open and nerve-sparing. The earlier analysis categorized patients according to the treatment they were randomized to receive, rather than the treatment they actually received. They did this because it eliminates "selection bias" - patients switched to the treatment that they or their doctors believed would benefit them most. Now, the authors report patient outcomes according to the treatment they actually received.

1. Treatment choice/ oncological outcomes

In the first year, 78% of patients received the treatment they were randomly assigned. Higher risk men chose radical treatment rather than AM. Conversely, men with low-risk PC were less likely to opt for EBRT.

In the ten years of follow-up, there were only 17 prostate cancer deaths out of 1643 men randomized in the trial. The pooled, adjusted risks were:

  • 69% lower risk of death for radical therapy (RP or EBRT) vs AM
  • 64% lower risk of metastases or death for radical therapy (RP or EBRT) vs AM
  • 77% lower risk of progression for radical therapy (RP or EBRT) vs AM
  • 47% lower risk of salvage ADT for radical therapy (RP or EBRT) vs AM
  • No statistically significant differences between RP and EBRT

2. Urinary Adverse Outcomes

a. Incontinence

This was a big issue for RP, of course, but not for AS or EBRT. The percent using one or more pads per day is one commonly used measure. As one can see in the following table, incontinence was highest at the 6-month time point, but had gotten somewhat better by the end of the first year. 24% were incontinent by the end of two years, with little improvement from that point. Incontinence increased slowly in the AM group as they elected to have radical treatment.


Table 1. Incontinence: The percent who used one or more pads per day

Time point
AM
RP
EBRT
Baseline
0%
1%
0%
6 months
0%
55%
1%
1 year
1%
32%
2%
2 years
3%
24%
2%
3 years
3%
23%
2%
4 years
5%
20%
2%
5 years
5%
20%
2%
6 years
7%
21%
2%

b. Nocturia

The researchers examined the question of whether nighttime urination was more frequent after therapy. On this dimension, only EBRT had a clinically detectable effect, and it was only at the 6 month mark. After that, it returned quickly to AM levels. RP returned to baseline level.

Table 2. Nocturia - Twice or more per night

Time point
AM
RP
EBRT
Baseline
20%
22%
20%
6 months
24%
35%
65%
1 year
23%
26%
36%
2 years
28%
23%
32%
3 years
31%
25%
32%
4 years
33%
25%
33%
5 years
35%
23%
36%
6 years
38%
25%
34%

3. Rectal Adverse Outcomes

The researchers asked the trial participants whether they had blood in their stools half the time or more. There were no discernable effects of AM or RP. Blood in stools peaked at a low level (8%) of those who had EBRT.

Table 3. Blood in stools more than half the time

Time point
AM
RP
EBRT
Baseline
1%
1%
1%
6 months
1%
1%
4%
1 year
1%
0%
4%
2 years
0%
1%
7%
3 years
1%
1%
8%
4 years
1%
1%
8%
5 years
2%
1%
8%
6 years
1%
2%
6%

4. Sexual Adverse Outcomes

This is one of the few trials that asked men detailed questions about their sexual function at baseline and for 6 years thereafter. One of the key measures of sexual function is the ability to have erections firm enough for intercourse. At baseline, about two-thirds of these 62 year old men (range 50-69), some with other comorbidities like diabetes, cardiovascular disease, and smoking, had suitable erectile function. 

None of the questionnaires asked about perceptions of penile shrinkage in length and girth, climacturia (urination at orgasm), or Peyronie's (abnormal penile curvature), which are often symptoms that affect sexual function post-prostatectomy. Nor do they ask about how the loss of ejaculate has affected sex. That is a certainty with surgery, a near-certainty after radiation, and is not affected by AM. Their definition of erectile function includes the effect of any erectile function aids (e.g. ED meds, injections, pumps, or implants) they may have been using.

For those randomized to RP, erectile function was possible for 5% at 6 months (remember: they all had nerve-sparing surgery). It recovered somewhat to as much as 13% at 2 years but did not recover appreciably beyond that. At every time point, their erectile function was significantly worse than the other treatment cohorts.

For the AM cohort, erectile function declined by 6 months and continued to deteriorate thereafter as they aged and elected to have radical therapies, predominantly surgery. 

For the EBRT cohort, erectile function had dropped to a minimum value of 18% at 6 months. This may be largely attributable to the fact that all of the men in the EBRT cohort had 3-6 months of ADT. It is unknown how much, if any, of their testosterone came back after that and how long it took to recover. Erectile function snapped back a bit post-ADT, getting as high as 34% at 3 years. At 6 years, potency was twice ads high as those who had RP. Again, this was based on the 3D-CRT technology, and is below the rates usually seen for this age group with IMRT, brachytherapy, or SBRT.

Table 4. Erectile function - the percent who had erections firm enough for intercourse

Time point
AM
RP
EBRT
Baseline
68%
66%
63%
6 months
59%
5%
18%
1 year
60%
6%
34%
2 years
54%
13%
32%
3 years
49%
14%
34%
4 years
43%
15%
31%
5 years
40%
16%
28%
6 years
35%
15%
29%


Myths Exploded by this study:

Myth #1: The side effects end up about the same for surgery or radiation
Myth #2: With surgery, you get the side effects all at once and steadily recover; with radiation, the side effects come on steadily and may hit you many years later.
Myth #3: Over time, erectile function is about the same for surgery and radiation. 

Thursday, December 19, 2019

Beyond PSMA - FAPI theranostics

Ideally, a new diagnostic and therapy ("theranostic") will have the following qualities:
  • it will be theranostic for all cancer (high sensitivity)
  • it will not be theranostic of anything that isn't cancer (high specificity)
In my previous article (see this link), we saw how PSMA heterogeneity can lead to treatment failure. PSMA is pretty specific, except for the salivary glands, the kidneys, and a few other places where expression is low. There is an opportunity to create ligands that are more sensitive and more specific.

Cancer is a tissue-based disease too

We often think of cancer as a cell-based disease: some rogue cells go wild, become immortal, and replicate out of control (see "The Hallmarks of Cancer"). In 1889, Stephen Paget put forth the "seed and soil" hypothesis: the cancer (the seed) thrives in "congenial soil." Not only does the seed find such soil, we have since learned that it actively creates its soil. This led to a new understanding of cancer as a tissue-based disease (see this link). What we call the "microenvironment" of the cancer is not just a passive player supporting the cancer cells; it actively sends signals to some cells (via extracellular vesicles - small "bubbles" containing microRNAs, enzymes, and essential proto-oncogenes) that cause them to become cancerous, and other cells to become supportive tissue - collagen, fat, blood vessels and nerves (collectively called stroma). They also suppress immune infiltration, attract regulatory T cells and certain kinds of macrophages that prevent immune response, and release cytokines that may cause or suppress inflammatory  response. The "reactive stroma" allows the tumor to grow and expand. This starts a positive feedback loop that enables the tumor (a collection of cancer cells and their stroma) to grow relentlessly.

Cancer-Associated Fibroblasts (CAF)

Fibroblasts are the most common cells in our connective tissue, which is the most prevalent tissue in our bodies. They create the collagen, fibronectin, the ground substance, adipose tissue, cytokines, growth factors, and other proteins that makes up the extracellular matrix that supports tissue architecture. When one cuts one's fingers, fibroblasts are activated and create the structure needed for the wound to heal. Fibroblasts are involved in cell adhesion, growth, migration and differentiation. Because they give rise to many different kinds of cell-precursers and proteins, they may be thought of as stem-cell-like (mesenchymal). The interested reader may wish to read this.

When cancer cells in the prostate go awry, they may, at some point go from being normal epithelial cells to being mesenchymal cells (called the epithelial-to-mesenchymal transition or EMT). EMT cells are capable of traveling outside of the prostate, where they can grow and clump into metastatic tumors, replete with cancer-associated fibroblasts (CAFs). The tumor can be thought of as a wound that doesn't finish healing and continually creates more wounds. In some cancers, 90% of the tumor volume is the stroma.

The tumor stroma can impair drug deliver, participate in drug resistance, and change the very nature of the cancer within (its phenotype). The stroma is where immunological agents and vascular-targeted agents have their effect (or lack of effect in the case of prostate cancer). See this link for a detailed discussion. It is also potentially targetable if it has a specific characteristic protein.

Fibroblast Activating Protein Inhibitor (FAPI)

There are several characteristic proteins in CAFs. One called Fibroblast Activating Protein (FAP) seems to be particularly useful. It is highly specific - it has only been found in cancers of epithelial origin (like prostate cancer), and never in healthy tissue. Immunohistochemical analysis of tumors has demonstrated a strong correlation between high FAP expression and worse prognosis. It has also been found in damaged tissue: inflamed tissues as in rheumatoid arthritis, myocardial infarction, liver cirrhosis, and atherosclerosis.

Uwe Haberkorn and researchers at the University of Heidelberg have synthesized a FAP inhibitor (FAPI) that seems to inhibit production of CAFs specifically and thoroughly.  Not only does it inhibit progression in mouse models, but it seems to "fix" the problems associated with the cancer stromal compartment - imperviousness to immunotherapies and angiogenesis inhibitors. They are fine-tuning the ligand to be more sensitive and specific, and to last long enough in clinical use for theranostic applications.

Kratochwil et al. reported on the Ga-68-FAPI uptake in 28 different tumor types in 80 patients, in whom FDG, PSMA or other PET scans failed to detect much cancer. Good uptake was seen for almost all solid tumors. Above average uptake was seen for sarcoma, salivary, esophageal, cholangiocellular carcinoma, breast, lung, prostate, pancreatic, thymus, head and neck, ovarian, desmoid, chordoma, and colorectal cancer.

Lindner et al. reported on two metastatic breast cancer patients treated with Y-90-FAPI-04 as a proof of concept. They both reported an immediate reduction in pain. Dr. Baum at Bad Berka has treated 10 patients with a single low dose of Lu-177-FAP-2286. It accumulated in tumors, and had no associated toxicity. There was some symptomatic relief in some patients, and he plans to give them a second injection.

Recently, we saw how two PET indicators were more sensitive than one. In that study, a GRPR-targeted ligand was paired in the same molecule with an integrin-targeted ligand. Integrins are created downstream from fibroblasts. GRPR is found in prostate cancer cells but is also highly expressed in gastrointestinal and CNS tissues. This limits its usefulness as a therapeutic target. However, the concept of double therapeutic targets is potentially useful for prostate cancer, where both PSMA and FAPI may be targeted.

Clinical Trials

In the US, preliminary clinical trials of FAPI-targeted PET indicators have begun.


Jeremie Calais plans to have an expanded study at UCLA sometime next year, which I will report on. So far, there are no therapeutic trials of Lu-177-FAPI that I am aware of, although the Haberkorn group may well be doing exploratory work.









Sunday, December 15, 2019

Why Lutetium-177-PSMA treatment sometimes may not help, and may even harm

Lu-177-PSMA usually improves survival

We've seen in a couple of small trials in Germany and Australia that Lu-177-PSMA seemed to provide better than expected survival. In Germany, median overall survival was 12.9 months across 104 patients. In Australia, median overall survival was 13.3 months across 50 treated patients. In both trials, all or almost all patients had already received taxane chemotherapy and either enzalutamide or abiraterone. There was no control group in either trial, so we can only guess at what overall survival would have been without the therapy.

In the "ALSYMPCA" trial of Xofigo, among the subgroup of patients who had received docetaxel for their painful mCRPC (see this link),  median overall survival was 14.4 months with Xofigo vs. 11.3 months with placebo. The ALSYMPCA trial was conducted before abiraterone and enzalutamide were approved, so it is impossible to know how prior treatment with one of those might have changed survival.

In a recent trial of Jevtana as a third-line therapy, after docetaxel and either abiraterone or enzalutamide, median overall survival was 13.6 months for Jevtana vs. 11.6 months for the other second-line hormonal.

So, in heavily pre-treated patients, Lu-177-PSMA seems to improve survival about as well as Xofigo or Jevtana when used as a third-line therapy. We will get a better handle on the actual survival benefit when we get the results of the VISION trial next year.

PSA is not always a good indicator of effectiveness, as has been found for Xofigo and Provenge. Lu-177-PSMA reduced PSA in about 2/3 of treated patients in most studies. That leaves about 1/3 of patients who derived no benefit (even though they had PSMA-avid tumors), and waterfall plots showed that a few patients had large increases in PSA following PSMA-targeted therapy.

It is worth noting that the PSMA protein contributes to the survival of the cancer, and just the PSMA ligand that attaches to it has some activity in delaying progression, even without a radioactive component (similar to the way an anti-androgen attaches to the androgen receptor, delaying progression). It is also worth noting that ADT initially increases PSMA expression, but decreases its expression with continued use.

The opportunities are:
  • to select patients who are likely to benefit
  • give alternative therapies (like Jevtana) to patients who are unlikely to benefit
  • provide adjuvant therapies that may increase survival

PSMA avidity - optimal point in time

It has long been known that PSMA is a moving target. The advent of PSMA PET scans has enabled us to track PSMA expression. Cancers that express a lot of PSMA (called PSMA-avid tumors) can be distinguished from cancers that express very little. Radiologists determine avidity by comparing the uptake of the tracer in cells that express PSMA to the uptake of the tracer in cells known to not express PSMA. Early low-grade prostate cancer does not express PSMA at all. Higher grade prostate cancer may express some PSMA. PSMA expression really starts to take off when the cancer metastasizes, although it is highly variable between patients. About 90-95% of metastatic men express at least some PSMA on their prostate cancer cells. At some point, however, as genomic breakdown continues, PSMA is no longer expressed by metastases. Thus, there is an optimal point for treating each patient with PSMA-targeted therapy. Treatment too early or too late, may exert selective pressure on the predominant non-PSMA-types, allowing them to take over.

Michael Hofman and others at the Peter MacCallum Cancer Center in Melbourne (see this presentation and this link) have initiated several clinical trials using Lu-177-PSMA at earlier stages of disease progression:

  • #lutectomy trial (Declan Murphy,  PI) is treating PSMA-avid high-risk patients with Lu-177-PSMA, followed by prostatectomy and pelvic lymph node dissection
  • #upfrontPSMA (Arun Asad, PI) is treating patients first diagnosed with high volume metastases with Lu-177-PSMA + ADT + docetaxel vs ADT + docetaxel.

Other opportunities for early use include Lu-177-PSMA treatment for those in the following settings:
active surveillance

  • persistent PSA after prostatectomy
  • salvage treatment after first recurrence
  • salvage treatment after second recurrence
  • metastatic CRPC before docetaxel or advanced hormonal therapies
  • non-metastastic (on bone scan/CT) CRPC before docetaxel or advanced hormonal therapies

Centers in Germany may be willing to treat patients per protocol (i.e., outside of a clinical trial) in some of those situations.

Repopulation

In radiobiology, one of the ways in which radiation can fail to destroy cancer is called repopulation. It means that when radiation kills some cancer cells but leaves many behind, the remaining ones now have access to space in which to expand and access to nutrients and oxygen that the other cancer cells had deprived them of. Paradoxically, the tumor can then grow faster than it ever would have before the treatment. This is sometimes seen with rapidly growing tumors, as some head and neck cancers. They sometimes irradiate those cancers multiple times a day to prevent repopulation.

Repopulation is never seen with X-ray (or proton) treatment of relatively slow-growing prostate cancers. X-rays penetrate throughout the prostate and kill all the cancer there. If there is any survival of an oxygen-deprived tumor core, it will be killed by the next fraction of X-rays in a day or two. However, Lu-177 emits beta rays that may only penetrate to about 125 cells around each target. Ac-225 (also sometimes used in PSMA therapy) only kills about 8 cells around each target. With such short-range killing, there is a real danger of repopulation if there are insufficient PSMA targets within the tumor. Multiple treatments are usually not given for several weeks, and the tumors may have changed by then.

PSMA heterogeneity

What we have learned recently is that not only does PSMA expression change over time, but in a given patient, some tumors may express PSMA and some may not. Moreover, even within a single tumor, some cells may express PSMA and some may not.

Paschalis et al. looked at the degree of PSMA expression of 60 patients with metastatic castration-resistant prostate cancer (mCRPC). They also looked at tissue samples of 38 of them taken when they were diagnosed with hormone-sensitive prostate cancer (HSPC). To detect the amount of PSMA expressed, they used an antibody stain that attaches to the part of the PSMA protein that lies above the cellular membrane. They rated the tumors "0" if there was no PSMA up to "300" if all cells expressed PSMA. They also performed a genomic analysis, looking for mutations in over 100 genes associated with DNA-repair defects.

Among the tumor samples from men with HSPC they found:
  • 42% of the 38 men with HSPC  had no PSMA at diagnosis - it only emerged later
  • 5 of the 6 HSPC men diagnosed with Gleason score 6 or 7 had little or no PSMA expression at that time
  • About half of 30 HSPC men diagnosed with Gleason score 8-10 had little or no PSMA expression at that time
  • Those who expressed PSMA had a worse prognosis
  • Expression of PSMA varied greatly (heterogeneous) between patients
  • Expression of PSMA varied greatly between biopsy samples from the same patient
  • The higher the PSMA expression in a patient, the greater the amount of PSMA heterogeneity
Among the tumor samples from the 60 men with mCRPC they found:
  • PSMA expression had increased from when they were diagnosed with HSPC
  • Half of the tumors with no PSMA at HSPC diagnosis continued to have no PSMA
  • 73% expressed PSMA; 27% did not - only 1 of whom had neuroendocrine prostate cancer
  • 84% of those expressing PSMA exhibited marked PSMA heterogeneity
  • Heterogeneous patterns were identified:
    • PSMA positive and negative cells interspersed in a single area
    • PSMA-positive islands in a sea of PSMA-negative cells
    • PSMA-positive regions separated by >2 mm from PSMA-negative regions
    • Some metastases wholly PSMA-positive, some wholly PSMA-negative in the same patient
  • Bone and lymph node metastases had similar PSMA expression; liver metastases (none neuroendocrine) had lower PSMA expression
Analysis of DNA-repair defects revealed:

  • mCRPC patients with DNA-repair defects had higher PSMA expression
  • HSPC patients without DNA-repair defects were less likely to become PSMA-positive
  • Patients treated with PARP inhibitors were more likely to respond if they were PSMA-positive
  • For validation, in a separate sample of tumors, those with DNA-repair defects were found to have much higher PSMA expression than those without such defects. This was especially true for somatic mutations in BRCA2, ATM, and dMMR.
  • PSMA was downregulated in androgen-independent basal cancer cells (resistant to advanced anti-androgens) and neuroendocrine cells.

The significance of this study is that it may explain why about a third of PSMA-avid patients do not respond to Lu-177-PSMA therapy. The emitted beta particles may kill cells within about 125 cells from where they are attached at the PSMA site. Thus cells that do not express PSMA that are more than 2 mm from a PSMA-avid site will not be killed (see "Repopulation" above).

The authors hypothesize that DNA-damage repair defects cause PSMA to proliferate. If they are right, a PARP inhibitor (like olaparib), which has also been found to be effective when there are DNA-repair defects (see this link), may be able to increase the efficacy of PSMA treatment. This is the subject of an ongoing clinical trial.

Practical detection of heterogeneity/ clinical trials

Now that we know that heterogeneity can impact Lu-177-PSMA effectiveness, it behooves us to find a way of determining the degree of heterogeneity without doing a biopsy of every single metastatic site. One way is to give each patient two PET scans, so they could see the sites that exhibited PSMA expression as well as the sites that exhibited high uptake on an FDG PET scan.

It is futile to offer PSMA-targeted therapy if there are many sites that show up only on an FDG PET scan but few sites that display uptake of PSMA. It also may be futile to treat patients that show some sites where PSMA and FDG sites do not overlap - "discordant." On the other hand, where there is a high degree of overlap between FDG and PSMA - "concordant" - the PSMA radiotherapy will kill both cancers simultaneously. Of course, the ideal candidate would display only highly PSMA-avid sites.  Thang et al. reported on the survival of 30 patients who were treated with Lu-177-PSMA (who were either high PSMA/low FDG or concordant, compared to 16 patients who were excluded based on lack of PSMA (8 patients) or a high degree of discordant sites (8 patients). All patients were heavily pretreated.

  • Treated patients survived 13.3 months (median)
  • Untreated patients survived 2.5 months (median)

It is unknown whether the survival of the excluded patients might have been longer or shorter had they received treatment. It is possible that discordant patients may benefit from sequenced (before or after) or concomitant treatment with:
It is possible that such adjuvant treatment may decrease the population of discordant sites, and minimize repopulation effects.

Based on this new knowledge, it is recommended that patients who are good candidates for Lu-177-PSMA radiotherapy have both a PSMA PET/CT scan and an FDG PET/CT at around the same time. FDG PET scans are generally covered by insurance; PSMA PET scans are not covered by insurance yet.

Saturday, December 7, 2019

Optimal chemohormonal sequencing for mCRPC MAY be Taxotere->Zytiga->Jevtana->Xtandi

(1) Taxotere (docetaxel) first

In a retrospective study presented at the Society for Urologic Oncology meeting,  researchers at the Mayo Clinic reported on 112 patients with metastatic castration-resistant prostate cancer (mCRPC).

  • Group A (80 men) had docetaxel (Taxotere) followed by one of the second-line hormonal therapies: either abiraterone (Zytiga) or enzalutamide (Xtandi)
  • Group B (32 men) had a second-line hormonal therapy followed by Taxotere.
  • Bone metastases were more common in Group B (87%) than Group A (58%)

Three-year survival was:

  • cancer-specific survival: 87% Group A vs 64% Group B
  • overall survival: 82% Group A vs 61% Group B
  • results were similar for men with high volume metastases, excluding those with lymph node-only
This was not a prospective randomized clinical trial. It reaches a different conclusion from a couple of earlier retrospective analyses.  Sonpavde et al.  reported an analysis of 1445 patients at VA hospitals. They found no difference in overall survival among those who started with taxanes vs. those that started with a second-line hormonal therapy. In a study at Johns Hopkins, Maughan et al. reported that there were no statistically significant differences in total progression-free survival related to the order in which the medicines (Taxotere or Zytiga) were given. Both studies adjusted for disease characteristics.

In the STAMPEDE trial of newly diagnosed men with metastatic hormone-sensitive prostate cancer (mHSPC), there was no difference in survival among men who were randomized to get Taxotere or Zytiga first (see this link). The difference in the Mayo study may be due to "selection bias" in the retrospective study - Group A may have received Taxotere first because they were healthier, and more likely to survive.

But even if the survival difference is an artifact of the study methodology, there are other reasons to do Taxotere first:
  • Side effects are less when chemo is given earlier
  • In fact, side effects are no worse for chemo or Zytiga (see this link). The differences are in the kinds of side effects, but not in their seriousness.
  • By starting with 6 infusions of Taxotere, one is able to use Zytiga after only 15 weeks; but if one starts with Zytiga, it may be 3 years before Taxotere can be tried (see this link).
There doesn't seem to be any cross-resistance between taxanes and Zytiga (as there is between Zytiga and Xtandi). A pilot trial combined the two without finding excessive toxicity, and larger trials of the combination are ongoing; for example, this one. However, a randomized trial of docetaxel+Xtandi vs docetaxel alone found there was no survival advantage to combining them, but toxicity was higher with the combination.

(2) Zytiga (abiraterone) before Xtandi (enzalutamide)

Khalaf et al reported the results of a randomized Phase 2 trial in British Columbia. 202 newly diagnosed mCRPC men were randomized to either Zytiga or Xtandi first. After progressing on the first therapy, they were given the second therapy (cross-over).
  • The Zytiga-first men progressed after 19 months vs 15 months in the Xtandi-first group
  • After cross-over, PSA was reduced by more than 30% in 36% of those who had Xtandi-second vs only in 4% of those who had Zytiga-second
Until we have a larger study that follows men for the rest of their lives, we can assume that the extended progression-free time among those who use Zytiga before Xtandi will translate to extended survival.

It's worth noting that it has been found that Zytiga can work a median of 10 months longer if one switches from prednisone (10 mg/day) to dexamethasone (0.5 mg/day) when progression begins (see this link).

A trial combining Zytiga and Xtandi found there was no benefit to combining the two drugs, but toxicity was worse than Xtandi alone. A small trial of Zytiga monotherapy (without ADT) showed that it can reduce testosterone on its own and another small trial suggested that oncological outcomes were not compromised by the monotherapy.

(3) Jevtana (cabazitaxel) third

Jevtana is currently FDA-approved for men in whom Taxotere has already been tried and failed. Jevtana and Taxotere (both taxanes) have been found to be virtually identical in oncological results when given as first-line therapy (see this link) with a similar degree of toxicity. If Taxotere and one of the second-line hormonal therapies (Zytiga or Xtandi) have already been tried, is it better to try the other second-line hormonal therapy next or is Jevtana a better choice for the third therapy? De Wit et al. found the answer.

They randomized patients who already had Taxotere and one of the two second-line hormonal to receive either the other second-line hormonal or Jevtana.
  • 126 received Jevtana
  • 58 received Zytiga
  • 66 received Xtandi
After 9.2 months median follow-up, 
  • Imaging-based progression-free survival was 8.0 months for Jevtana vs 3.7 months for the hormonal therapy
  • The advantage for Jevtana was maintained regardless of risk characteristics and treatment history
  • The advantage for Jevtana was true regardless of which hormonal therapy it was compared to.
  • Overall survival was 13.6 months for Jevtana vs 11.0 months for hormonals.
  • PSA was reduced by at least 50% in 36% of men using Jevtana vs 14% using hormonals.
  • Tumors shrank in 37% of men using Jevtana vs 12% using hormonals
  • Serious adverse events of any grade were similar for all therapies at 39%.
  • Adverse events leading to death were more frequent with the hormonals (11%) than Jevtana (6%)
  • Pain was improved more by Jevtana (in 45% of men) than by hormonals (in 19% of men)
  • Skeletal events (fractures, spinal compression) occurred more frequently among those taking hormonals (51%) than Jevtana (29%)

Jevtana was at least as good or had a clear advantage on every measure of success.

(4) Xtandi fourth

There is some evidence that taxanes (like Taxotere or Jevtana) can reverse one mode of hormonal resistance (AR-V7 splice variance). Research continues on methods to reverse resistance (e.g., see subsection - "what's next?"). Although there is known cross-resistance between Zytiga and Xtandi, Xtandi usually works at least for a while after Zytiga.

Other medicines

Other medicines approved for men with mCRPC include older anti-androgens (like bicalutamide), Xofigo, Provenge, and Keytruda (but only in the rare event of MSI-hi/dMMR). It would save time if any of these could safely be piggybacked on top of another therapy.

Older anti-androgens (like Casodex or flutamide) are still used sometimes in the mCRPC setting, mostly in combination with a GnRH agonist (like Lupron). The combination is somewhat more beneficial (see this link) than a GnRH agonist alone, and provides a short-term benefit at low cost. Sometimes, the cancer learns how to feed on the anti-androgen, and removing it leads to a reduction in PSA (called antiandrogen withdrawal syndrome). Newer antiandrogens (like Xtandi) don't seem to do this.

It is unknown where the newest antiandrogens fit into sequencing. Erleada and Nubeqa have been approved for other indications, but not yet for mCRPC. Others (like proxalutamide) haven't yet cleared the first hurdle.

Xofigo cannot be prescribed after any visceral metastases have been detected, although it may work well on the bone metastases nevertheless. It works better sooner rather than later, but a trial combining it with Zytiga was stopped early because of a high rate of skeletal events. Early results of a new trial combining Xofigo and Xtandi show that adding a bone-protective agent (Xgeva or Zometa)  can ameliorate the problem.

Provenge may synergize with radiotherapies or chemo because they present many cancer antigens for the amped up immune system to tune into. There is evidence that an abscopal effect (systemic immune response) may be augmented. Other immunotherapies, which show little therapeutic promise alone, may be beneficial in combination with chemo or other therapies.

PARP inhibitors are in clinical trials, and seem to be especially effective when there are BRCA1/2 mutations (germline or somatic). Several clinical trials are combing carboplatin with taxanes. Transdermal estrogen is inexpensive and is available now. Optimal sequencing or combinations are yet to be determined. 

Lu-177-PSMA-617 and similar radiopharmaceuticals are in ongoing trials. The VISION trial used it only among men who had been pre-treated with chemo and Zytiga or Xtandi. If it gets FDA approval, it will be limited to use after those other treatments. However, trials are ongoing for earlier use and in combination therapy. There is probably an optimum time for use of PSMA-directed therapies. Combination with different PSMA-targeted radionuclides (like Ac-225), and with multiple membrane targets are being explored.

There are myriad other potential therapies in clinical trials. Many are pathway growth inhibitors that may work best in combinations. Therapies tailored to specific genomic mutations are in their infancy.


Tuesday, October 1, 2019

Olaparib slows progression in men with BRCA gene mutations

The PROfound Trial has reported (here) significant improvements in progression-free survival in men with BRCA2, BRCA1, and ATM gene mutations who took the PARP inhibitor, olaparib (Lynparza). BRCA2, BRCA1, and ATM germline gene mutations are found in about 8% of men with metastatic castration-resistant prostate cancer (mCRPC). The study also included men in whom those genes were mutated in their tumors (called "somatic" mutations). PARP inhibitors inhibit an enzyme that supports the survival of DNA-damaged cancer cells. Lynparza is FDA-approved for ovarian cancer and breast cancer. Other FDA-approved PARP inhibitors comprise Rubraca (rucaparib) and Zejula (niraparib) for ovarian cancer, and Talzena (talaparib) for breast cancer. They are all in clinical trials for prostate cancer (see this link).

The PROfound Trial (details here) compared the effectiveness of Lynparza to either Xtandi or Zytiga (cohort B) in men who had already failed one of them. They compared the two groups in men who had somatic mutations in BRCA 1/2 or ATM (Cohort A, n=245) and in men who had somatic mutations in any of 12 other DNA-repair genes (Cohort B, n=142), and in men who had any of the 15 DNA-repair mutations (Cohort A+B, n=387). The trial was conducted at 229 sites. The 12 other DNA-repair mutated genes were BARD1, BRIP1, CDK12, CHK1/2, FANCL, PALB2, PPP2R2A, RAD51B/C/D, and RAD54L.

Their interim (median 1 year) findings comparing Lynparza vs Xtandi/Zytiga were as follows:

Median radiographic progression-free survival (rPFS):
  • Cohort A: 7.4 months vs 3.6 months (HR=0.34, p<0.0001)
  • Cohort A+B: 5.8 months vs 3.5 months (HR=0.49, p<0.0001)
Among the combined cohorts (A+B):
  • 6-month rPFS: 60% vs 23%
  • 12-month rPFS: 28% vs 9%
  • Objective Response Rate: 33% vs 2%
  • Time to pain progression: not reached vs 10 months
Median overall survival (OS):
  • Cohort A: 18.5 months vs 15.1 months (HR=0.64, p=0.017)
  • Cohort A+B: 17.5 months vs 14.3 months (HR=0.67, p=0.006)
Adverse Events:
  • Lynparza patients had more anemia, nausea, fatigue & asthenia, decreased appetite, diarrhea/constipation, vomiting, and respiratory issues.
  • 16.4% discontinued with Lynparza vs 8.5% discontinued with hormonal therapy
  • Nevertheless, they stuck with Lynparza for 7.4 months  vs 3.9 months with hormonal therapy
In a small study (12 BRCA1/2-mutant, 5 ATM-mutant), Marshall et al. reported activity in men with BRCA1/2 mutations, but not ATM mutations:

  • Reduction of PSA by at least 50% was seen in 83% of men with BRCA1/2 mutations vs 0% of men with ATM mutations.
  • Progression-free survival was 12.3 months in men with BRCA1/2 mutations vs 3.3 months in men with ATM mutations.


Similarly good responses among men with bi-allelic (both genes mutated) BRCA1/2 mutations vs other DNA-repair mutations were reported in a Phase 2 trial of niraparib. The FDA has granted it "breakthrough therapy" designation.

Men with CDK12 mutations (one of the DNA repair mutations in Cohort B of the PROfound trial) unsurprisingly did not respond to PARP inhibitors (see this link).

Preliminary results of the TRITON 2 clinical trial of rucaparib in men with DNA-damage repair (DDR) deficiencies (either germline or somatic) were also reported. Clinical benefit (the % who had no radiographic progression and stayed with rucaparib) at 6 months and 12 months for each of the DDR genes found were as follows:

  • BRCA1/2: 56% (47/84) at 6 mos., 25% (6/53) at 12 mos.
  • ATM: 29% (14/48) at 6 mos., 8% (2/25) at 12 mos.
  • CDK12: 21% (3/14) at 6 mos., 7% (1/14) at 12 mos.
  • CHK2: 67% (2/3) at 6 mos., 0% (0/1) at 12 mos.
  • Other DDR: 50% (6/12) at 6 mos., 33% (3/9) at 12 mos.
There was high treatment-related toxicity in these heavily pre-treated patients:
  • Treatment interruption or dose reduction in 54%
  • Discontinuation in 9.5%
  • Most common serious (grade 3+) adverse events: anemia (18%), fatigue (11%), thrombocytopenia (6%)
  • 5 deaths (3%)
Triton 3 (comparing rucaparib to abiraterone, enzalutamide or docetaxel) is ongoing.

Early results of the TALAPRO-1 trial of talaparib have been presented. The 43 patients were previously treated with docetaxel, and half had cabazitaxel too.

  • The overall objective response rate (ORR) and radiographic progression-free survival (rPFS) was 26% and 5.6 months, respectively.
  • Those with the BRCA 1 or 2 mutation (n=20) had a 50% ORR and 8.2-month rPFS
  • Those with the ATM mutation (n=14) had a 7% ORR and 3.5-month rPFS
  • The most common treatment-emergent adverse events (≥20%) were anemia, nausea, asthenia, decreased appetite, constipation, and decreased platelet count.


I would guess that the FDA will want to see the planned three-year results for olaparib, which are expected in 2021, although Astra-Zeneca may try to obtain fast-tracked approval based on this interim analysis. Meanwhile, patients are encouraged to get the relatively inexpensive ($249) germline test, or if negative for actionable mutations, a genomic test of a tumor biopsy or of cell-free DNA (from a blood test).

Sunday, September 29, 2019

"Adjuvant" similar to "Early Salvage" Radiation Outcome in Meta-analysis

Although at least three randomized clinical trials have told us that adjuvant radiation after prostatectomy often affords better results than just taking a "wait-and-see" approach, most radiation oncologists have been reluctant to immediately treat every man with poor post-prostatectomy pathology results (positive margins, stage T3/4, high Gleason score).  Now, some early combined results (called a meta-analysis) of three more randomized clinical trials suggest that oncological outcomes may be no worse if men wait to be treated until certain PSA cut-offs are reached.

The three randomized clinical trials were RADICALS-RT (UK & Canada), GETUG-AFU-17 (France), and RAVES (Australia & NZ). The meta-analysis, called "ARTISTIC" (critique here). comprised 2151 men, of whom 1074 were randomized to adjuvant radiation and 1077 were randomized to early salvage radiation. There have been 5 years of follow-up so far. ARTISTIC analyzed the early data based on "event-free survival," which for the most part meant freedom from a PSA-defined recurrence after radiation.

"Adjuvant" radiation (ART) was defined by all three trials as treatment within 6 months of prostatectomy. Note that this can be longer than the "immediate" treatment often given.

"Early salvage" radiation (eSRT) was defined variously as treatment when PSA ≥ 0.1ng/ml or 3 consecutive rises (RADICALS-RT), PSA≥0.2 ng/ml and rising (GETUG-AFU-17), or PSA≥0.2 ng/ml (RAVES).

Patients in all three trials had positive surgical margins, extracapsular extension, or penetration into the seminal vesicles. Most patients were intermediate risk:

  • Most (77%) had a Gleason score of 7
  • Very few (9-17%) had a Gleason score of 8-10
  • About 1 in 5 had seminal vesicle invasion


After 5 years of median follow-up:

  • Event-free (mostly PSA) survival was about the same for ART and eSRT (HR=1.1, p=0.47)


In addition, there were some top-line results presented for the largest study, RADICALS-RT:

  • At 5 years, biochemical progression-free survival was 85% for ART and 88% for eSRT (p=0.56, not statistically different)
  • Urinary incontinence at one year was 5.3% for ART vs 2.7% for eSRT (p=0.008, statistically different)
  • Serious or life-threatening urethral stricture was 8% for ART vs 5% for eSRT (p=0.03, statistically different)


Pelvic lymph nodes

If pelvic lymph node dissection during prostatectomy revealed any positive nodes, or if scans suggest enlarged, cancerous pelvic lymph nodes, there is no question that adjuvant radiation is required. RTOG 0534 showed that salvage radiation of pelvic lymph nodes with adjuvant ADT increase progression-free survival even when there were no detected cancerous lymph nodes, but only if PSA was high enough.

It is never worth waiting for PSA to rise to a point where newer PET scans can detect metastases just to find out where the largest sites of recurrence are. That would be a self-fulfilling prophesy - the goal is curative treatment before the cancer has time to metastasize. A/SRT must be given to the prostate bed, and possibly an extended pelvic lymph node field. The patient must treat what is still too small to see.

Adjuvant ADT

Other arms of RADICALS, not yet reported, explored the effect of various durations of adjuvant hormone therapy. GETUG-AFU-16 proved that adding at least 6 months of ADT improved results of SRT. RTOG 0534 also showed that adding ADT to SRT was often beneficial. But RTOG 9601 showed that adjuvant ADT did not improve results 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.

Radiation Dose

GETUG-AFU-17 and RADICALS-RT used a radiation dose of 66 Gy in 33 treatments. RADICALS-RT also allowed a moderately hypofractionated dose (52.2 Gy in 20 treatments). RAVES used a slightly lower dose: 64 Gy in 32 treatments. A recent analysis by Chris King suggested that these doses may be inadequate, or that a higher dose may not require adjuvant ADT. The effect of the higher dose on toxicity using the best linacs is unknown.

High Risk/Decipher

Most of the men in these trials were originally intermediate risk. It is entirely possible that originally high-risk men (Gleason 8-10, PSA≥20 or cT3/T4) may benefit more from ART rather than eSRT.  Men who were originally low risk (Gleason 6 and PSA<10 and T1/2) may be able to wait longer or indefinitely before SRT.

If the Decipher score is very high, that should also be taken into account in deciding between ART and eSRT. Genome Dx also provides scores that suggest whether the cancer is amenable to SRT, but those scores have yet to be prospectively validated.

We are starting to get a better handle on the ART vs eSRT decision, but none of what we have learned gives us hard-and-fast guidelines. Thee trial results do provide more fodder for discussion between the patient and his radiation oncologist.