Combination Treatments for Hormone Sensitive PC (mHSPC): Trusting a Meta-Analysis

[MateoBeach]

Here, below, is a meta-analysis: a systematic review and analysis combining a number of prospective randomized clinical trials. This one is looking at which treatment, when added to standard ADT, produces the best results (overall and progression free survival) for metastatic hormone sensitive disease.

But first I want to raise the question of which is better: A single prospective randomized clinical trial (RCT), or a meta-analysis of multiple such RCTs? There are different opinions: no surprise. It seems to me that meta-analysis has the advantage of reducing variability between RCTs of the same treatment(s) vs alternative treatments or placebo in different populations of patients.

ascopost.com/issues/june-10...

The disadvantage of meta-analysis is the problem of bias being introduced because the studies included are selected retrospectively. There is also "data-availability bias" and lack of unpublished studies that are more likely to have been negative. Also lower quality studies can dilute higher quality studies, resulting in lower quality overall. In, short: RCTs eliminate bias, meta-analysis (can) increase bias. We need to take this into consideration. Meta-analysis of well done and similar RCTs can provide great confirmation of positive findings. That seems to be the case here:

sciencedirect.com/science/a...

Indirect Comparisons of Efficacy between Combination Approaches in Metastatic Hormone-sensitive Prostate Cancer: A Systematic Review and Network Meta-analysis

Review Article

European Urology, Volume 77, Issue 3, November 2019, Pages 365-372

Niranjan J. Sathianathen, Samantha Koschel, Isaac A. Thangasamy, Jiasian Teh, Omar Alghazo, Georgiana Butcher, Harriet Howard, Jada Kapoor, Nathan Lawrentschuk, Shankar Siva, Arun Azad, Ben Tran, Damien Bolton, Declan G. Murphy

Context

There have been substantial changes in the management of men with metastatic hormone-sensitive prostate cancer (mHSPC) over the past 5+ yr, with upfront combination therapies replacing androgen-deprivation therapy (ADT) alone. A range of therapies have entered the space with no clear answer regarding their comparative efficacy.

Objective

To perform a systematic review and network meta-analysis to characterise the comparative efficacy of combination approaches in men with mHSPC.

Evidence acquisition

We searched multiple databases and abstracts of major meetings up to June 2019 for randomised trials of patients receiving first-line therapy for metastatic disease, a combination of ADT and one (or more) of taxane-based chemotherapy, and androgen receptor-targeted therapies. The primary endpoint was overall survival (OS) and we evaluated progression-free survival as a secondary outcome. We performed subgroup analysis based on the volume of disease.

Evidence synthesis

We found seven trials that met our eligibility criteria using either docetaxel, abiraterone acetate, enzalutamide, or apalutamide in combination with ADT. All agents in combination with ADT were shown to be superior to ADT alone; enzalutamide + ADT had the lowest absolute hazard ratio compared with ADT only (hazards ratio 0.53, 95% confidence interval 0.37–0.75), and an estimated 76.9% probability that it is the preferred treatment to prolong OS compared with other combination treatments, or with ADT alone. Enzalutamide appeared to have better OS compared with docetaxel in men with low-volume disease, but there was no difference in other comparisons.

Conclusions

Combination therapy with any of docetaxel, abiraterone acetate, enzalutamide, or apalutamide provides a significant OS benefit when compared with ADT alone. We did not identify significant differences in OS between different combination therapies. Subtle differences between these options provide clinicians considerable flexibility when selecting options for individual patients.

Patient summary

Many men with metastatic, hormone-sensitive prostate cancer should be managed with upfront combination therapy instead of androgen-deprivation therapy alone. Clinicians may consider many factors during the decision-making process, and thus management should be tailored for patients individually.

Paul / MateoBeach

[Hidden]

Amen! But tell my MO this and he laughs . SOC only baby. Don’t rock the ship they say ???

[MateoBeach in reply to Hidden]

Ha! 😆 then see my next post just now about the SOC. 👍

[Hidden in reply to MateoBeach]

You’re on a roll big guy! Thanks I’ll check it out . 😎🌵

[DarkEnergy]

@Schwah may have a few things to say about this.

Me too to an extent:

healthunlocked.com/advanced...

After 3 months of treatment vacation: May 19th blood draw has PSA 0.09, from <0.02 and T 9 ng/dL, from < 3 ng/dL. Will draw PSA monthly to gauge velocity.

[MateoBeach in reply to DarkEnergy]

Good plan. So far so good. Trim sails when you need to.

[DarkEnergy in reply to MateoBeach]

I don't have a life that can wait for clinical trials results, I will do my best to move on...

[Gearhead]

If only there was a good agreed-on way to measure QOL, and they could find trials where both QOL and OS were measured, and then they did a meta-analysis of those trials... I would love to read that study. Would the same conclusion be reached?

[MateoBeach in reply to Gearhead]

QOL is beginning and more and more being considered in trial results. Fortunately and about time. See the latest BAT trial in this regard. Video on Pjosheas’s post.

[maley2711]

Didn't Allen just yesterday post the results of an RCT now being conducted.....showing triple combination to be the best so far?

[Schwah in reply to maley2711]

You are correct. That is what Dark energy was referring to. Chemo/ADT/Zytega combo provenTo be better than any of the two mentioned above. And it wasn’t even close. More than double the time to CRPC and/or PFS. BOTH dark Energy and I did all 3 before this trial because our MOs thought out of the SOC box. It did seem logical at the time, if A plus B is better then A alone and A plus C is better than A alone, then it seems like A plus B plus C would be the best. And it was. Interestingly I learned that most doctors at the big medical institutions either won’t or can’t advise anything out of standard of care. When I got a second opinion at UCLA three years ago on the potential use of this triple cocktail, she said she could not recommend that even though it sounded like it could make sense. I emailed her The new study showing how well it worked yesterday. Her reply “Yes, this study had to come for us to use.” Must be an internal policy at many of these institutions.

Schwah

[cesces]

meta-analysis is to generate hypotheses.

Randomized clinical trials are to prove or disprove hypotheses.

[Masirah]

Correct me if I am wrong, but the ADT is aimed at reducing testosterone, which is said to feed PCa. I have recently turned 70 and last year was diagnosed with an aggressive prostate cancer. I was prescribed tablets to reduce my testosterone, even though the urologist didn't actually test my testosterone levels. I have read that from the age of 30ish, the level of testosterone declines in males, so why do they insist on ADT? I felt dreadful whilst taking the tablets and so took myself off them. I started to research the subject and saw a lecture from an Israeli professor of urology, who advised against this form of treatment, saying it was dangerous. He mentioned it risked blood clots and stroke. I spoke to my oncologist and she wasn't alarmed that I wasn't continuing with the treatment and told me I could expect to live at least another 10 years, barring any other illnesses, or accidents. What are the views of other contributors on this subject? I wish Paul (a.k.a. MateoBeach) all the best.

[MateoBeach]

You have Gleason 9 prostate cancer with perineural invasion, meaning it is a very aggressive form. So you need to treat it aggressively or it will kill you. You are not appropriate for Watchful Waiting. You do not fit accepted criteria for that because of the Gleason score. This is not a low grade form that you can just live with. Androgen (testosterone) deprivation therapy, ADT, is a proven foundational treatment to stop progression and growth of PC, for a time. Then it stops working and other treatments must be added, or combined treatments from the start. Unfortunately the side effects of ADT are terrible for most, as you found out. We all hate it but it helps keep us alive. But there are effective ways to mitigate those SEs.

Fortunately, you are not yet metastatic on your scans. Time for aggressive action. Surgery (prostatectomy) or radiation. You should consult with a very experienced urologist surgeon, and with a radiation oncologist (RO) right away. Do not wait- get it before it spreads if you can. The most effective form of radiation RT combines external beam X-ray treatments with brachytherapy (radioactive seeds). This is called Brachy-boost. You will need to be on ADT for some time to help the radiation kill the cancer.