(UroToday.com) The 2023 EAU annual meeting included a session discussing clinically meaningful questions in the management of advanced, hormone-sensitive prostate cancer, featuring a debate regarding the added value of docetaxel in combination with ADT and ARPI for the treatment of mHSPC.
Yes – Docetaxel in Combination with ADT and ARPI
The position of yes, docetaxel should be added in combination with ADT and ARPI was taken by Dr. Ursula Vogl. Dr. Vogl started by highlighting that the management of mHSPC is an evolving systemic treatment paradigm:
Three trials have assessed the “triplet therapy approach” of ADT + docetaxel +/- novel hormonal agents in mHSPC: ENZAMET (ADT + docetaxel +/- enzalutamide),1 PEACE-1 (ADT + standard of care [docetaxel] +/- abiraterone),2 and ARASENS (ADT + docetaxel +/- darolutamide).3 As follows is a summary of the rPFS and OS results for these 3 trials:
Dr. Vogl notes that what we know from high level evidence is two-fold:
- ADT + docetaxel, ADT + abiraterone, and ADT + enzalutamide or apalutamide >> ADT
- ADT + docetaxel + abiraterone, and ADT + docetaxel + darolutamide >> ADT + docetaxel
With regards to ADT + ARPI + 6 cycles of docetaxel versus ADT + ARPI, Dr. Vogl correctly states that we don’t know which is better, considering that there has not been a head to head randomized controlled clinical trial. The rationale for triplet therapy up front in the mHSPC setting is as follows:
When considering if there is added value of docetaxel in combination with ADT + ARPI for the treatment of mHSPC, Dr. Vogl notes that we need to do a simple oncological evaluation:
- Do we assume our patient is fit enough for 6 cycles of 75 mg/m2 q21 docetaxel +/- GCSF support?
- Does the patient’s clinical presentation (ie. de novo metastatic) give us the rationale that the patient would benefit?
- Do we have other features of aggressiveness that might eradicate the clones leading to potential early resistance to ADT and ARPI?
If the answer to these questions is yes, then Dr. Vogl sees a potentially significant added value to implementing docetaxel into the ADT + ARPI treatment strategy in mHSPC. At the APCCC 2022 meeting, three questions were asked of the experts that are relevant to this topic: In which patients with synchronous mHSPC that are chemotherapy fit do you recommend triplet therapy ADT + docetaxel + ARPI? 70% responded only in high volume patients; 26% responded that they usually do not recommend this combination; 4% responded in the majority of patients, independent of disease volume. The second question was: In which patients with metachronous mHSPC that are chemotherapy fit do you recommend the triplet therapy ADT + docetaxel + ARPI? 58% responded only in high volume patients; 37% responded that they usually do not recommend this combination; 5% responded in the majority of patients, independent of disease volume. The third question was: In which patients with synchronous low volume (on conventional imaging) mHSPC do you recommend a triplet systemic therapy, irrespective of a decision about local radiation therapy? 68% responded that they do not recommend triplet therapy in these patients; 30% responded in low volume but “borderline” high risk features (one or more of Gleason 8-10, 3-4 bone metastases, extensive lymph node involvement, disease that cannot be covered by SBRT); 2% responded in the majority of patients.
Both the NCCN and EAU guidelines underline the added value of docetaxel + ADT and ARPI giving the same level of evidence (category 1) for both therapeutic strategies. Dr. Vogl concluded her portion of the debate by concluding that no time soon will we have the answer as to whether triplet therapy is better than ADT + ARPI.
No – Docetaxel in Combination with ADT and ARPI
The position of no, docetaxel should not be added in combination with ADT and ARPI was taken by Dr. Maria De Santis who started by stating that not everything is ever for everyone. The benefit of the triplet combination treatment in some better prognosis subgroups with mHSPC is not clear. For example, if we look at the survival outcomes of the ADT control arms, we see that some patients will do ok without triplet therapy:
- Synchronous and high volume: 3 years
- Synchronous and low volume: 4.5 years
- Metachronous and high volume: 4.5 years
- Metachronous and low volume: ~8 years
In ARASENS, only 86 participants (13.2%) in the darolutamide arm and 82 participants (12.5%) in the placebo arm had recurrent metastatic disease. Node only disease made up 3.5% of the darolutamide arm and 2.4% of the placebo arm, thus no meaningful conclusions can be made. In PEACE-1, only de novo metastatic disease with bone or visceral metastases were enrolled, thus no conclusions can be made about node only metastases or recurrent disease. As highlighted in the following figure, low volume patients in PEACE-1 did not derive an OS benefit (HR 0.93, 95% CI 0.69-1.28):
Dr. De Santis notes that our strongest tools are ADT + ARSIs, given that there is a significant OS benefit from doublet therapy for mHSPC:
There are also important other questions that remain to be answered: 1) What about ADT + darolutamide as the backbone? 2) Which patient would benefit from the addition of docetaxel to darolutamide?
With regards to personalized treatment in 2023, the PEACE-6 program is running several clinical trials in mHSPC, with treatment selection driven by tumor, PSA, and clinical parameters:
Since the effect of docetaxel does not appear consistent across disease states, the field needs a predictive biomarker for tailored docetaxel use. Patient selection by genetics is primarily driven by BRCA2 germline carriers/mutations with cancer specific survival greater when treated with first-line abiraterone/enzalutamide versus taxanes in mCRPC. The predictive value of SPOP+ mutations led to improved outcomes with abiraterone in the CRPC. Given that mHSPC retrospective data suggests that SPOP+ gene mutations have improved survival in de novo mHSPC receiving ADT alone, perhaps this is an opportunity for de-escalation of therapy.
There are several mHSPC trials implementing molecular markers:
- Earlier use of PARP inhibitors in combinations?
- BRCA2/DRD: AMPLITIUDE (NCT037486641), TALAPRO-3 (NCT04821622), and STAMPEDE
- AKT-inhibitors?
- PTEN loss: CAPItello-281 (NCT04493853)
- PSMA-radioligand therapy?
- PSMA positive: PSMAddition (NCT04720157)
- CDK-inhibitors?
- Cell cycle: CYCLONE 3 testing abiraterone + prednisone +/- LY2835219 (CDK4&6 inhibitor)
Dr. De Santis concluded her portion of the debate with the following concluding statements:
- ADT plus one of the approved ARPIs (doublet) therapy is standard of care for all eligible mHSPC patients
- Trials are ongoing for mHSPC aimed at further de-escalating therapy and personalizing therapy
- Triplet therapy is not for the majority of patients
Debater 1: Ursula M. Vogl, MD, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
Debater 2: Maria De Santis, MD, Charite Universitaetsmedizin, Berlin, Germany
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2023 European Association of Urology (EAU) Annual Meeting, Milan, IT, Fri, Mar 10 – Mon, Mar 13, 2023.
References
- Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. N Engl J Med 2019 Jul 11;381(2):121-131.
- Fizazi K, Foulon S, Carles J, Roubaud G, et al. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): A multicentre, open-label, randomized, phase 3 study with a 2 x 2 factorial design. Lancet. 2022 Apr 30;399(10336):1695-1707.
- Smith MR, Hussain M, Saad F, et al. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. N Engl J Med. 2022 Mar 24;386(12):1132-1142.