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). However, it can improve prognosis in men who have low PSA (<0.4ng/ml), high Gleason grade (8-10), and good performance status (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.

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 Docetaxel + Second Line Hormonal Therapy

Triplet therapy means combining docetaxel with a second-generation hormonal medication and ADT. Triplets with abiraterone, darolutamide, and enzalutamide have been found to confer greater benefit than docetaxel+ADT in newly-diagnosed metastatic men (discussed here). The benefit held with darolutamide (in the ARASENS trial) even in men with low metastatic burden. Presumably, there will be a similar benefit with abiraterone when the PEACE1 trial matures.

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, when men are already castration-resistant, combining docetaxel and Xtandi slowed progression but did not result in a survival advantage over docetaxel alone in the Phase II CHEIRON trial. The Phase III PRESIDE trial proved that docetaxel could reverse Xtandi resistance, but did not increase survival.

Again, earlier use of docetaxel is better.

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.

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). In the STAMPEDE trial, median (50%) survival was 76.6 months with Zytiga vs 45.7 months with ADT alone.  So, early Zytiga increased median survival by 31 months, reducing mortality by 38%; 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 radiation may make the cancer more susceptible to immune attack (see this link). However, chemo, which also generates antigen fragments, has failed to stimulate an immunotherapy response from checkpoint inhibitors. The combination of docetaxel with a checkpoint inhibitor has proven to be ineffective in this trial and this one. 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. This is called the "tumor sink effect" and was noted in this study and this one.

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.


  1. This is a very helpful paper. I will take time to absorb it all but it provides a great, evidence-based, road-map for decisions on treatment timing. Thank you Allen

  2. No one digests and summarizes better, thank you, Tall One
    As for early use of docetaxel section, I am surprised that
    --Median time to radiographic progression 9 years, higher than I would have expected.
    --And then 40-45 percent died within the next three years, faster than I would have thought.
    Still digesting most of the post–-clearly written but my intellectual capacity is limited..

  3. Allen thank you so much for sharing your valuable knowledge with us. Much appreciated. Serhat

  4. Add my kudos to the the above. You are the voice of reason on Health Unlocked and your depth of knowledge is appreciated. I have a very specific question to ask regarding a recommendation and or guidance on how to proceed with my treatment - is this a proper forum for my question(s)?

    1. You can ask here, publicly on HealthUnlocked or private message on HealthUnlocked.

  5. Allen,
    Thank you for your response. Before my question, I will provide a brief history with the specifics I'm thinking will be helpful. Currently 74yrs old and in excellent health. PCa Dx in Mar 2014; RALP pathology G9 with T3bNOMO, ECE. Post surgery PSA 1.5 but then declined to 0.22 and 0.1 prior to initiating 9 months Lupron monotherapy Jun2014 and 35 IMRT sessions in October 2014. Subsequent PSAs were undetectable (with 2 small ultrasensitive indications that dropped back to undetectable in 2017). In 2018 I experienced 6 successive PSA increases topping at 0.846; then two drops 0.742 and 0.136 before again increasing to 0.268 and in Jan this year 1.09. Have had Claris genetic testing with no significant variations.
    On the recommendation of an experienced MO (who expressed concern about a possible mutation to neuroendocrine PCa), and motivated in part by a reluctance to resume ADT, I enrolled in a clinical trial at the City of Hope Duarte CA testing the efficacy of the f18 DCFPyl PSMA PET/CT. Scan was performed Mar 01. COH PSA just prior to the scan 1.02 (different Lab). Results were a very small (8mm) indication on one pelvic lymph node that the clinical trial team would like to biopsy.
    I am strongly considering having the biopsy (CT guided by interventional radiologist) with the belief that the risk/reward is acceptable, but am having trouble decifering the impact of what treatment modification would result - it would seem ADT in some form would be appropriate and SOC in any event? I have been told that the biopsy would not provide sufficient tissue to provide genetic characteristics. I am still trying to get a location on the lymph node. Any ideas on additional questions I should ask or alternate courses of action I should consider?

    1. Were your pelvic LNs already treated when you had salvage radiation?

  6. Thank you for your response. LN's not previously treated. ECE was in the left nerve bundle which was removed and cauterized during the RALP. IMRT to the prostate bed only. I do not yet know the location of the suspicious LN and/or if SBRT or whole pelvic LM radiation is an option.

    1. I think you should consider having ALL your pelvic LNs irradiated (up through the common iliacs). There is undoubtedly more cancer that is too small to show up on the DCFPyL scan. I doubt you will learn much from a biopsy.

  7. Am I correct in assuming that the whole pelvic LN irradiation would be accompanied by some variation of ADT? I am thinking that the next PSA might provide a clue as to how aggressive the next level of treatment should be.

    1. If there are known cancerous lymph nodes, long-term adjuvant ADT is usually given.

  8. Hi Allen Edel,

    I have been following your posts for a long time be it on healing well, health unlocked or on this blog and value all that you do to help others. I need your help for my father. He has been recently diagnosed with stage 4 with Mets to distant lymph nodes and just one bone met in the pelvic region. He was treated for piles 10 years ago and had problem of constipation and went to his gastroent assuming it to be a relapse of piles, who referred him to get a PSA test done. The psa was 114.16 and the biopsy revealed a Gleason of 4+4=8, PSMA pet scan showed multiple Mets to lymph nodes and one bone. He got the bilateral orchiectomy done and began on Casodex. 3 weeks Post the orchiectomy and Casodex the psa lowered to 4.66 ng/ml. The urologist advised to continue Casodex n get psa retested post 3 months along with a sonography. The oncologist we met earlier had said he may consider Abiraterone. I am confused as to which approach to follow for him ? Early use of Abiraterone? Or sequential use of it post the psa starts to increase. Please advise

    1. Please read this:

  9. Tall Allen, you are a very bright light in bringing relevant info to the forefront, and always with the background studies, tests and trials.
    Thanks much for your help.