Indirect Comparisons of Efficacy Between Combination Approaches in Metastatic Hormone-Sensitive Prostate Cancer

[Balsam01]

TAKE-HOME MESSAGE

•This systematic review characterized the comparative efficacy of combination approaches in men with hormone-sensitive metastatic prostate cancer. In all, seven trials met 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. Enzalutamide appeared to be associated with better overall survival compared with docetaxel in men with low-volume disease, but there was no difference in other comparisons.

•The authors concluded that combination therapy with any of docetaxel, abiraterone acetate, enzalutamide, or apalutamide provides a significant overall survival benefit when compared with ADT alone.

– Gautam Jayram, MD



Urology 

Written by Fred Saad MD, FRCS

For over 70 years, androgen deprivation therapy (ADT) has been the standard of care for metastatic castration-sensitive prostate cancer (mCSPC). Over time, almost all will progress to a metastatic castration-resistant prostate cancer (mCRPC) state and eventually die of the disease. Several new agents have enabled men with mCRPC to live longer with a better quality of life; however, the improvements in outcomes have been relatively modest. The addition of some of these agents to ADT in the setting of metastatic hormone-sensitive prostate cancer has resulted in significantly improved outcomes. This meta-analysis confirms that all the combinations are better than ADT alone in mCSPC.

Should everyone be treated? I believe and agree with the authors that all patients with high-risk and/or high-volume mCSPC should be offered immediate additional therapy with ADT. However, for low-burden metastatic disease, the hormonally based therapies appear to be the preferred option and some patients may not need lifelong combination therapy. Personalizing the approach for these patients will be our next challenge. Until then, options may include sequential treatment in patients who rapidly achieve undetectable serum PSA levels with ADT plus local therapy. The other choice may be an intensive approach for all of these patients, with treatment discontinuation after 2 to 3 years of treatment in patients having a complete response. We may actually revisit the intermittent approach for mCSPC using optimal combination therapy. Given the efficacy and long survivals that can be achieved, we will actually need to start considering life expectancy when treating low-volume/low-risk mCSPC. One thing is certain—these advances are pushing the field forward and this is great news for our patients.

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.

 European Association of Urology

Indirect Comparisons of Efficacy Between Combination Approaches in Metastatic Hormone-Sensitive Prostate Cancer: A Systematic Review and Network Meta-Analysis

Eur Urol 2019 Oct 31;[EPub Ahead of Print], NJ Sathianathen, S Koschel, IA Thangasamy, J Teh, O Alghazo, G Butcher, H Howard, J Kapoor, N Lawrentschuk, S Siva, A Azad, B Tran, D Bolton, DG Murphy

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

[Hawk56]

After surgery (T2CNoMX, SV, ECE and margins negative, GS 4+4 and 10% involvement) in March 2014, I had BCR in Sep 15, did SRT in March 2016, that failed. I had discussed doing combination therapy with my medical team given my GS and time to BCR after surgery, they talked me out of it, not enough long term evidence.

After SRT failed when PSA was .7 then 1.0 a month later and MY PSADT and PSAV were exponentially increasing I went to see the head of urology at KU Medical Center here in Kansas City. He wanted to start on ADT alone, no imagining, no combination therapy.

Having learned my lesson from listening to my medical team about combination therapy I thanked him, more or less fired him and went to Mayo in January 2017. The C11 Choline scan showed four pelvic lymph nodes bu no organ or bone involvement.

I started a combined treatment regimen of 18 months of Lupron, six cycle of taxotere and 25 more radiation treatments. PSA dropped from 4.8 to .88 with the first Lupron and taxotere and to <.1 after that. T dropped to ,3 and stayed there.

Last Lupron shot was in May 2018, it cleared my system by September as T was 135 in October and 482 in February 2019. Last PSA labs in August this year was .05.

The combined regimen was no walk in the park but since completing treatment the SEs are gone, fatigue, hot flashes, muscle and joint stiffness, testicle and penile shrinkage and blood values have returned to normal ranges.

Am I cured, not likely.

How long with I progression free period be, don't know.

We are basically in active surveillance, have a plan when to image and with clinical data decide on treatment when that becomes necessary. I stay active and eat healthy.

So for me, combination therapy makes sense, overwhelm PCA in its early stages vice lone agent treatment. Not smart enough to understand the chemistry and biology behind the theory but intuitively it makes sense, synergy!

Kevin

[jsmdwp in reply to Hawk56]

Best of luck to you Kevin. Do you mind sharing the name(s) of your Mayo doctor(s)? Thank you.

[Hawk56 in reply to jsmdwp]

Dr. Kwon is my Mayo doctor.