Showing posts with label docetaxel. Show all posts
Showing posts with label docetaxel. Show all posts

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 in the CARD randomized clinical trial..

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.

(Update 9/16/20) Fizazi et al. reported the Quality of Life (QOL) outcomes of the CARD trial (above).
  • Pain response was better with Jevtana  than hormonals (46% vs 19%)
  • Time to pain progression was about twice as long with Jevtana (hazard ratio (HR)= 0.55)
  • Time to next symptomatic skeletal event was similarly longer with Jevtana (HR= 0.59)
  • Function scores and time to deterioration of function scores (e.g., ability to self-care, perform usual activities, mobility, mental status, sense of well-being, social/family well-being) were better with Jevtana



(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 don't seem to do this as much, although it has been observed in a minority of patients for abiraterone and enzalutamide.

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 some evidence to suggest that it synergizes with Xofigo. 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. (Update: see this link.) 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.


Sunday, February 3, 2019

Timing is everything with docetaxel (and hormone therapy and probably with immunotherapy and radiopharmaceuticals too)

The conventional wisdom with cancer is that "earlier is better." As cancers progress, they mutate: there are many more genetic errors in older cancers than in younger ones (see this link). Because of this, a therapy that may work well against a cancer in one stage of its development, may not work at all in an earlier or a later stage.

Prostate cancer is one of the most slow-growing of cancers in its early stages. This is why we can take so much time to decide on initial treatment, even in high-risk cases (see this link). It is also why low-risk men may safely choose active surveillance over immediate radical therapy. Progression is only weakly correlated with time since diagnosis, even for recurrences (see this link).

Early Use of Docetaxel

We have already seen that docetaxel is of limited (if any) use when combined with radiation therapy and ADT for high-risk cancer patients (see this link). It is also ineffective when combined with prostatectomy and ADT for high-risk cancer patients (see this link).

Oudard et al. conducted a randomized clinical trial of docetaxel+ADT vs ADT-alone in non-metastatic men with a recurrence after primary treatment. All 250 patients were "high risk," which was defined as at least one of the following:
  • Gleason score ≥ 8
  • PSA velocity > 0.75 ng/ml/year
  • PSADT ≤ 6 months
  • time to recurrence ≤ 12 months
Previous treatments were:
  • 73% had prior prostatectomy
  • 27% had prior primary radiotherapy ± ADT
  • 60% of men who had a prostatectomy also had salvage EBRT
The outcomes were as follows:
  • Median PSA progression-free survival was no different:19 months if they got docetaxel, 20 months if they didn't
  • Median time to radiographic progression was no different: 9 years in each group
  • There was no difference in 12-year overall survival rates: 60% in the docetaxel group, 55% in the no-docetaxel group. (The docetaxel group was 2 years younger)
  • Adverse hematological events from docetaxel included neutropenia (48%), febrile neutropenia (8%) and thrombocytopenia (3%)
CHAARTED showed that the survival increase attributable to docetaxel in recently-diagnosed, metastatic men was only observed among men with a high volume of metastases, but not among men with a low volume of metastases. "High volume" was defined as visceral metastases or 4 or more bone mets with at least one beyond the pelvis or vertebrae. 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.

One small observational study suggested that docetaxel may benefit men who are castration-resistant but are not yet detectably metastatic. At the other end of the progression spectrum, in men who are both metastatic and castration-resistant, docetaxel added 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.

Docetaxel remains effective even after second-line hormonals (e.g., Zytiga, Xtandi) have stopped working. In fact, there have been cases where use of docetaxel has reversed resistance to them caused by the AR-V7 splice variant. However, combining docetaxel and Xtandi did not result in a survival advantage over docetaxel alone in a randomized clinical trial.

The "sweet spot" for docetaxel seems to be after there are detectable metastases but before castration resistance is fully established. Used earlier, it seems to have no effect in most men; used later, it is still effective, but less so.


Early Use of Hormone Therapy

It is well established that hormone therapy alone adds nothing to the survival of localized prostate cancer (see this link and this one). We also know that hormone therapy adds nothing to the effectiveness of radiation therapy for favorable risk prostate cancer (see this link and this one and this one). Even with recurrent prostate cancer post-prostatectomy, a major randomized clinical trial (RTOG 9601)  found that adding long-term antiandrogen therapy to radiation did not increase outcomes as much in men who had Gleason score ≤ 7, PSA ≤ 0.7 ng/ml or negative surgical margins.

However, an early analysis of the TOAD randomized clinical trial suggests that using androgen ablation on men who are recurrent after prostatectomy but not yet detectably metastatic may have a net survival benefit over the selective pressure it exerts towards castration resistance. In fact, men who started on ADT earlier developed castration resistance significantly later. This effect was also noted in the TROG 03.04 RADAR trial. The authors wrote, "The cumulative incidence of transition to castration resistance was significantly lower in men receiving [longer term ADT with their EBRT]."


Early Use of Second-line Hormone Therapy

We have learned that the use of abiraterone (Zytiga) in newly-diagnosed metastatic men increases survival markedly over waiting. 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 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 by16.8 months. Abiraterone was equally effective regardless of the number of metastases or whether they were classified as higher or lower risk (see this link).

Enzalutamide (Xtandi) is probably also beneficial if used earlier. A non-randomized clinical trial of early use of Xtandi showed it is very effective if used earlier (see this link), and a Phase 3 trial for its use in hormone-sensitive prostate cancer has had good results, according to a press release.

The FDA has approved apalutamide (Erleada) and enzalutamide (Xtandi) for use in non-metastatic castration-resistant prostate cancer. Darolutamide and abiraterone (Zytiga) will probably also be approved for this indication. Non-metastatic castration-resistant prostate cancer is probably an early version of metastatic castration-resistant prostate cancer, where micrometastases have not yet grown large enough to become detectable on a bone scan/CT.

Clinical trials suggest or are in process to determine if there is a role for advanced hormonal agents even earlier; for example in any of the following early settings:

• as part of an active surveillance protocol for men with favorable risk prostate cancer (see this link)
• adjuvant to radiation in high-risk localized prostate cancer (see this link)
• when it as advanced to only as far as pelvic lymph nodes (Stage N1 M0) (see this link)
• when it is recurrent but not yet detectably metastatic (see this link)

Early Use of Immunotherapy

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 in one small study (see this link). There are several clinical trials to help determine whether immunotherapy can play a role in extending the time that a man can stay on active surveillance (see this link and this one and this one).

In the "CHECKMATE 650" clinical trial of a combination of the two checkpoint inhibitor-type immunotherapies, nivolumab (Opdivo) and ipilimumab (Yervoy), there was some response (in 25% of pre-chemo men and 10% of post chemo men) from the combination, but no response from either drug alone in earlier trials. However, all of the responders  (60% of the pre-chemo group and 40% of the post-chemo group) had a high mutational burden and/or showed the presence of PD-L1 in the tumors (33% of the pre-chemo group and 19% of the post chemo group). Conversely, none of the men who had low mutational burden or PD-L1 had any response to the combination therapy. Toxicity was unacceptably high. This indicates that the cancer must evolve to a high degree of genetic breakdown before such therapies become effective. Early use causes unacceptable toxicity without any survival benefit.

At some point, cancer cells start displaying antigens that can be recognized by the immune system as "non-self," but it is not clear when that occurs in prostate cancer progression. Perhaps the fragments generated by chemo or radiation may make the cancer more susceptible to immune attack (see this link). It is also unclear when immune infiltration into tumors can occur, when checkpoint inhibitors (like PD-L1) begin to appear, and when regulatory T cells are overwhelmed by killer T-cells. Pro- and anti-inflammatory cytokines undoubtedly play a role in immune signaling and may occur at different stages.

Early Use of Radiopharmaceuticals

The ideal candidate for Xofigo will get all 6 treatments, preferably earlier, while bone health is still good (see this link). It has been found to work better on smaller tumors, so it is best used earlier rather than later (see this link). Because the combination of Xofigo and Zytiga caused excessive fractures and deaths (see this link), they can't be given simultaneously, at least not without a bone-preserving agent (like Zometa or Xgeva). Since a full cycle is completed in 24 weeks, taking Xofigo before Zytiga allows one to get the benefit of both in less time.

We do not know enough about the natural history of PSMA yet. We don't know when the PSMA protein first appears on the tumor surface. It has been detected in "high risk" patients, and is more often associated with higher grade cancer and in men with higher PSAs (see this link and this one). It as been detected in up to 95% of metastases. PSMA-based PET scans (Ga-68-PSMA-11 or DCFPyL) are used to check for PSMA-avidity before treatment. Without significant PSMA, the radiopharmaceutical would have nothing to latch onto, and might cause toxicity with no cancer-killing benefit.

A pilot test in South Africa suggests that Ac-225-PSMA-617 had good efficacy in patients who were not heavily pretreated, but their cancer was more progressed when treated. A trial with Lu-177-PSMA found that overall survival was 11 months in patients who had already had chemo (and were more progressed) and was 27 months in chemo-naive patients (who were also less progressed). Earlier seems to be better.


Although it is generally true that earlier treatment is better, we have learned that there are exceptions. There is tremendous individual variation, and it is likely that the window of opportunity varies.

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 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 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.

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. An ongoing clinical trial is investigating whether Erleada combined with Zytiga extends survival in the relapsed hormone-sensitive 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.

One downside for Zytiga is cost. Zytiga costs about $9,000 per month and patients stayed on it for about 2 years so far (drug resistance is low when patients are ADT-naive). This use of Zytiga is now FDA-approved, so Medicare and most insurance should cover such early use. Lower cost generics have become available.

Docetaxel is available as a generic for a cost of about $9,000 for six 3-week cycles. Not only is it less expensive, it is covered by Medicare and all insurance. On a cost/benefit basis, it is preferable.

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?

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:
This will be recruiting soon:





Sunday, August 28, 2016

Docetaxel with primary radiation therapy for high risk prostate cancer


In 2004, the FDA approved docetaxel as the first chemotherapy drug proven to extend survival in metastatic hormone-refractory prostate cancer. Although the survival benefit was a modest 2.5 months, researchers launched clinical trials to determine whether the survival advantage could be increased by using docetaxel earlier in disease progression or by combining it with other therapies. Those trials are beginning to mature now.

Last year, the CHAARTED study demonstrated a 17-month survival advantage stemming from starting docetaxel at the same time as ADT in men with multiple metastases. However, another trial, GETUG-AFU 15, did not demonstrate a benefit. Last month, early reports of the STAMPEDE trial confirmed the benefit, which was 22 months among men with any metastases upon initial diagnosis. As in the CHAARTED trial, the evidence of benefit has not yet emerged among men with advanced cancer who did not yet evince metastases.

Several trials looked at combining docetaxel with radiation among men diagnosed with high risk localized prostate cancer. RTOG 0521 showed that the 4-year overall survival was 89% without docetaxel and 93% with it -- a statistically significant difference, but perhaps not as meaningful as we would have liked to see. There was a significant improvement in disease-free survival (65% vs. 55% at 6 years), and incidence of metastases at 6 years (9% vs 14%). It’s possible that with longer follow up, the difference in overall survival will increase in magnitude.

Another clinical trial, GETUG-12, was designed to find out whether chemotherapy (docetaxel + estramustine) pretreatment would provide a survival benefit when added to 3 years of ADT and RT begun 3 months from the start of chemo (in 87% of the patients). The study was described and early results given in 2010, so I will not go into the details again. However, some follow-up results have recently been published. (Update 12/4/2018Fizazi et al. report that after 9.6 years median follow-up, relapse-free survival was 11.6 years among those who received chemo versus 8.1 years among those who did not. Clinical/radiographic relapse-free survival was 13.9 years among those who received chemo versus 12.5 years among those who did not. Metastasis-free survival, prostate cancer- specific survival, and overall survival were not significantly different. They further report equal levels of late-term high-grade side effects in both groups, and no deaths attributable to the chemotherapy.

These are not yet the improvements in long-term survival that we eventually hope to see by adding docetaxel. The long wait for differences in survival once again highlights the very long natural history of the disease, even in men diagnosed with high-risk prostate cancer.


(Update: 6/28/2018) A Scandinavian trial (SPCG-13) reported no benefit to adding docetaxel after ADT+RT in unfavorable risk patients. 376 patients with unfavorable intermediate risk or high risk prostate cancer were randomized to receive either:

A. RT (at least 74 Gy) +ADT followed by docetaxel (75mg/m2) every 3 weeks for 6 cycles
B. RT (at least 74 Gy) +ADT

After 5 years of follow-up:
  • The rate of biochemical failure was the same for both groups, at about 30%.
  • There were 20 deaths in Group A, 9 attributable to prostate cancer
  • There were 23 deaths in Group B, 7 attributable to prostate cancer
  • Febrile neutropenia, which can be life-threatening, occurred in 17% of Group A.
Five years should be long enough to start seeing a difference in biochemical failure rates, but none was observed and the survival curves showed no signs of diverging. Based on this clinical trial, there was no benefit, but substantial risk to adding docetaxel after RT+ADT in unfavorable risk patients.

(Update 10/16/2018) A small (n=132) Spanish trial  (more details here) also found no benefit to adding docetaxel to RT+ADT in high risk men. Patients were randomized to one of two groups:

A. RT (74 Gy) +ADT (LHRH agonist for 3 years)
B. RT+ADT (as above) followed by 9 weekly cycles of docetaxel (20 mg/m2)

Patient characteristics were:
  • Stage T3/4: 81%
  • Gleason score ≥ 8: 77%
  • PSA>20: 29%
  • positive lymph nodes: 18%
After 5 years of follow-up:
  • Biochemical recurrence-free survival was not statistically different: 93% for Group A, 85% for Group B
  • Progression-free survival was not statistically different: 93% for Group A, 84% for Group B
  • Overall survival was not statistically different: 93% for Group A, 94% for Group B