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APCCC 2024: Ideal Sequence After ADT plus ARPI plus Docetaxel for mHSPC

(UroToday.com) The 2024 Advanced Prostate Cancer Consensus Conference (APCCC) meeting featured a session on the management of metastatic CRPC (mCRPC), and a presentation by Dr. Karim Fizazi discussing the ideal sequence after ADT + ARPI + docetaxel for treatment in the metastatic hormone-sensitive prostate cancer (mHSPC) setting. There’s no question that based on data from PEACE-11and ARASENS2 that triplet systemic therapy works in mHSPC:


In a pre-APCCC survey of 28 providers, Dr. Fizazi asked “Among your current patients with upfront (de novo) mHSPC, how often do you currently use the following systemic therapies?

  • Most common: ADT + docetaxel + ARPI (triplet therapy)
  • The second most common: ADT + ARPI
  • The third most common: ADT + docetaxel
  • Fourth most common: ADT alone

With regards to treatments used beyond progression in PEACE-1 post-triplet therapy, Dr. Fizazi asked the PEACE-1 statistician to compute patients that progressed after triplet therapy for presentation at APCCC (data cutoff April 23rd, 2024, unpublished data). There were 134 patients in the triplet arm that experienced a progression event. At least one life-prolonging treatment was received in 92% of patients that progressed. The most common treatments beyond progression for mCRPC was cabazitaxel (69%), enzalutamide (50%), docetaxel rechallenge (28%), and abiraterone (19%):
treatments used beyond progression in PEACE-1 post-triplet therapy
Dr. Fizazi notes that the main treatment options for mCRCP patients post-triplet therapy include cabazitaxel (CARD trial3), PARP inhibitors (primarily in the BRCA mutation population; PROfound trial4), and LuPSMA (VISION trial5):
cabazitaxel (CARD trial), PARP inhibitors (PROfound trial), and LuPSMA (VISION trial)
Dr. Fizazi notes that the RADIANT trial has fully accrued, assessing radium-223 as an option for mCRPC post-docetaxel and ARPI. This trial randomized patients to second ARPI versus radium-223 x 6 cycles:
RADIANT trial
Less appealing options after progression on triplet therapy for mHSPC include (i) a second ARPI, which typically does not work, even though the FDA encourages this sequence, and (ii) docetaxel rechallenge, which has a lower response rate than in docetaxel-naïve CRPC, has cumulative toxicity, and cabazitaxel is likely a better choice (20 mg/m2 + G-CSF support). So, how do we choose between the available options? Dr. Fizazi provided the following recommendations:

  1. BRCA alteration: preference for a PARP inhibitor
  2. MSI High: (strong) preference for a PD-1 inhibitor
  3. Strong PSMA expression: PSMA targeting
  4. Frail patient: Lu-PSMA, radium-223
  5. Long time since docetaxel use: Cabazitaxel? Second ARPI? 

Dr. Fizazi reminded the audience that no matter what you decide, please do not forget a bone-protecting agent (ie. denosumab)!no matter whatever you decide, please do not forget a bone protecting agent (ie. denosumab)
Finally, Dr. Fizazi notes that the biology will soon guide us for mCRPC post-triplet, based on oncogenic driver secondary alterations, bypass pathways, and lineage plasticity:oncogenic driver secondary alterations, bypass pathways, and lineage plasticity
Dr. Fizazi concluded his presentation discussing the ideal sequence after ADT + ARPI + docetaxel for treatment in the mHSPC setting by reminding us that there is life after triplets, and we should continue using them for mHSPC.

Presented by: Karim Fizazi, MD, PhD, Institut Gustave Roussy, University of Paris Saclay, Villejuif, France

Written by: Zachary Klaassen, MD, MSc - Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 Advanced Prostate Cancer Consensus Conference (APCCC) Meeting, Lugano, Switzerland, Thurs, Apr 25 - Sat, Apr 27, 2024. 

References:

  1. 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.
  2. 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.
  3. de Wit R, de Bono J, Sternberg CN, et al. Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer. N Engl J Med 2019 Dec 26;381(26):2506-2518.
  4. Hussain M, Mateo J, Fizazi K, et al. Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer.  N Engl J Med. 2020 Dec 10;383(24):2345-2357.
  5. Sartor O, de Bono J, Chi KN et al. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer.  N Engl J Med. 2021 Sep 16;385(12):1091-1103.