EAU 2021: Treatment Options for De-Novo mHSPC: Future: Personalized Medicine for mHSPC?

(UroToday.com) The treatment for metastatic hormone-sensitive prostate cancer plenary session at the European Association of Urology 2021 virtual annual meeting included a presentation by Dr. Karim Fizazi on personalized medicine for mHSPC. Dr. Fizazi notes that the concept of giving the right treatment to the right patient is mostly based on molecular analyses.

Perhaps one of the best examples of personalized medicine in advanced prostate cancer is the PROfound trial.¹ This study recruited men with mCRPC who had progressed on previous abiraterone acetate or enzalutamide administered at the time of non-metastatic castrate-resistant prostate cancer or at the time of metastatic castrate-sensitive prostate cancer. The FoundationOne CDx assay was used to identify alterations in one of 15 pre-specified genes involved in homologous recombination repair (BRCA 1/2, ATM, BRIP1, BARD1, CDK12, CHEK 1/2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, RAD54L). Cohort A had alterations in BRCA1, BRCA2, or ATM while Cohort B had alterations in any of the other 15 included genes. In both cohorts, patients were randomized 2:1 to Olaparib vs. abiraterone or enzalutamide. Among 4,425 patients who were screened, 387 of these patients met the eligibility criteria and were randomized. In an assessment of the primary outcome, there was significantly improved progression-free survival in Cohort A patients with mutations of BRCA1, BRCA2, or ATM (HR 0.34, 95% CI 0.25 to 0.47).

Additional trials in this disease space include a combination of capivasertib with a new hormonal agent in PTEN-deficient prostate cancer, as well as AKT inhibition, which has been tested in multiple settings, including mCRPC (ipatasertib + abiraterone), triple negative breast cancer, HR+ breast cancer, and endometrial cancer. The CAPItello-281 trial is a phase 3 trial to evaluate the efficacy and safety of capivasertib in combination with abiraterone, on a background of ADT, as a treatment for de novo mHSPC patients with PTEN-deficient tumors. As follows is the trial schema for this study:

This study is aiming to recruit 1,000 de novo mHSPC patients with PTEN loss confirmed centrally. An important stratification factor will be a combination of volume of disease according to CHAARTED criteria and the presence of visceral metastases.

PSMA is also a target for imaging and treatment, which is a transmembrane protein often highly expressed by prostate cancer cells. Additionally, it is not expressed in most normal tissues (except for salivary glands), and expression correlates with advanced disease. ¹⁷⁷Lu-PSMA-617 has recently been notable for targeted radioligand therapy, most recently with the publication of the VISION trial² showing a survival benefit of ¹⁷⁷Lu-PSMA-617 compared to standard of care among patients with mCRPC (HR 0.62, 95% CI 0.52-0.74):

As follows are the planned phase 3 trials of ¹⁷⁷Lu-PSMA-617 in earlier prostate cancer disease settings, including the PSMAddition trial in mHSPC:

Dr. Fizazi concluded his presentation with the following take-home messages:

There has been major progress in the treatment of mHSPC over the last five years
Still, most men with mHSPC will die from mCRPC
Only radiotherapy to the prostate is currently the only “personalized” approach for low-burden mHSPC
There are several appealing targets available:
- PSMA positive: Lu-PSMA in the PSMAddition trial
- DNA repair: PARP inhibitors
- PTEN loss: capivasertib

Presented by: Karim Fizazi, MD, PhD, Institut Gustave Roussy, Universite Paris-Saclay, Villejuif, France

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 2021 European Association of Urology, EAU 2021- Virtual Meeting, July 8-12, 2021.

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