(UroToday.com) The first day of the American Society for Clinical Oncology (ASCO) Genitourinary Cancer Symposium 2023 began with four talks highlighting key data that, from the perspective of medical oncologists, urologic oncologists, radiation oncologists, and pathologists, advanced the needle in prostate cancer care in 2023.
The first of these presentations was from Dr. Niven Mehra, highlighting key publications from the medical oncology point of view. He noted that, across all prostate cancer stages, there has been a shift in the use of next-generation hormonal agents from the end of the disease trajectory (metastatic castration-resistant prostate cancer) forward to metastatic castration sensitive prostate cancer to localized castration sensitive prostate cancer. Additionally, in both castration resistant prostate cancer (CRPC) and castration sensitive prostate cancer (CSPC) there has been a shift to rationale combination therapy to allow for even further intensification of therapy.
Overviewing his talk, he highlighted newly published data across the disease trajectory from high-risk non-metastatic castration sensitive disease in which data from the STAMPEDE platform, as published by Dr. Attard, examined treatment intensification with novel hormonal therapies (abiraterone acetate with or without enzalutamide) to de novo mHSPC in which we saw two pivotal randomized trials (PEACE-1 and ARASENS) looking at triplet intensification to first-line mCRPC in which publication of the PROpel trial provided the first data demonstrating the benefit of a combination therapy approach with both novel hormonal agents and PARP inhibitors.
To contextualize this discussion, he presented the case of a man diagnosed with locally advanced, high-grade localized prostate cancer, with a negative metastatic work-up using conventional imaging. He noted that the standard of care currently is two years of androgen deprivation therapy with prostate-directed radiotherapy. However, in a multi-disciplinary tumor conference, the alternative of intensification with a novel hormonal therapy was discussed on the basis of recent data from STAMPEDE.
As published in the Lancet this year, these data represent pre-specified analyses of two STAMPEDE trials focused on patients with high-risk non-metastatic disease. This could either be synchronous (either node positive or having at least two of T3/4, GG4-5, or PSA≥40ng/mL if node negative) or metachronous (PSA ≥4ng/mL with doubling time <6 months or PSA ≥20ng/mL with an ADT-free interval ≥12 months and a total prior ADT exposure ≤12 months). These patients were randomized to either abiraterone or abiraterone and enzalutamide as compared to standard of care, ADT alone. Given a lack of additional benefit of the combination of abiraterone and enzalutamide, the two comparisons were pooled for analyses.
Dr. Mehra noted that this study, enrolling nearly 2000 men, predominately comprised those with synchronous disease of whom the vast majority received prostate radiation therapy. As highlighted in the figures below, both metastasis-free survival (HR 0.53, 95% CI 0.44-0.64) and overall survival (HR 0.60, 95% CI 0.48-0.73) were improved in patients who received treatment intensification.
Based on these data, Dr. Mehra noted that the patient described previously was motivated for intensified therapy and received two years of abiraterone, three years of ADT, and hypofractionated prostate radiotherapy. However, he noted some clear uncertainties. First, PSMA-PET/CT is widely utilized in many institutions and it’s unclear the benefit of such intensification among patients who are non-metastatic based on PSMA imaging. Further, high risk patients with somewhat more favourable disease characteristics may have excellent outcomes with novel radiotherapy schemes in the absence of this systemic intensification.
Dr. Mehra then moved to the second case, highlighting an older man (77 years of age) presenting with high-volume bony metastatic castration sensitive prostate cancer with disease in the iliac bone, pubic bone, femur, and L3 vertebral body. Notably, he had some epidural involvement with disease. Dr. Mehra noted that, prior to this year, standard of care treatment comprised androgen deprivation therapy with either docetaxel or a novel hormonal agent. Given the high volume disease, prostate-directed radiotherapy would not be indicated. However, as of 2023, further treatment intensification with triplet therapy should be considered and discussed. Two large trials, PEACE-1 and ARASENS, provide the data for this approach.
As highlighted below, these trials differed somewhat in their methodology. While ARASENS was a relatively clean double-blind 1:1 randomized comparison, PEACE-1 utilizes as 2x2 factorial disease and employed an evolving standard of care over time.
In spite of methodologic differences, when comparing intensified treatment with ADT, docetaxel, and a novel hormonal agent (either abiraterone or darolutamide) to ADT and docetaxel, both studies showed a significant survival advantage.
Thus far, stratified data according to disease volume are somewhat immature. That presented from PEACE-1 demonstrated no benefit to date of the triplet approach compared to ADT and docetaxel in those with low-volume disease. Comparable data from the ARASENS trial will be presented at ASCO-GU 2023 by Dr. Hussain. Coming back to the case, Dr. Mehra noted that the patient was started on an LHRH antagonist and referred to a medical oncologist to discuss treatment intensification.
Finally, Dr. Mehra moved to a third case of a 72 year old man initially diagnosed with high-volume de novo metastatic hormone sensitive prostate cancer. He was treated with LHRH agonist and docetaxel initially but subsequently had PSA progression despite castrate testosterone levels. Notably, he had a family history remarkable for breast cancer in two sisters and his mother. However, germline analyses showed no mutations in relevant cancer predisposition genes (including BRCA1, BRCA2, PALB2, CHECK2, or ATM). Tumor somatic sequencing showed biallelic inactivation of ATM and PTEN. On re-staging at the time of castration resistance, there was evidence of 6-10 bony lesions, limited nodal involvement, as well as new adrenal and lung metastases.
Dr. Mehra noted that the phase 3 PROpel trial answers the question of the benefit of adding olaparib to abiraterone in the first-line treatment of mCRPC among all comers. To date, we have data from data cutoff 2, demonstrating significantly improved radiographic progression free survival for patients in the combination arm, with a trend towards improved overall survival, though this is not significant.
At this year’s ASCO GU meeting, final overall survival results from the third data cut-off will be presented that will help better understand the benefit of this treatment paradigm.
Importantly though, we already have data defined by homologous recombination repair (HRR) subgroup. While there was a significant radiographic progression-free survival benefit in both groups, the effect was greater (as may be expected) in the HRR mutant subgroup.
Thus, coming back to the case, this gentleman was offered a number of standard of care options including cabazitaxel, abiraterone or enzalutamide, or a PARP inhibitor monotherapy. However, based on data from PROpel, he was further offered the combination of abiraterone and olaparib, which he selected.
In conclusion, Dr. Mehra noted that multidisciplinary care is becoming more important for patients with prostate cancer as novel hormonal agents, chemotherapy and PARP inhibitors are all being used for intensification. Further, this intensification is moving earlier in the disease space, emphasizing the importance for timely referral. While these treatments are generally effective, biomarkers may enrich for responsiveness.
Presented by: Niven Mehra, MD, PhD, Radboud University Medical Center