The program of the 2022 ASCO Genitourinary Cancers Symposium, held as a virtual and an in-person event in San Francisco, California, February 17-19, included reports of clinical trials that addressed key questions in prostate cancer treatment. Speaking with GU Oncology Now, Catherine H. Marshall, MD, MPH, Assistant Professor of Oncology at The Johns Hopkins School of Medicine, Baltimore, focused on the presentations with the most immediate implications for prostate cancer management.
Dr Marshall: Studies presented during the oral abstract session highlighted two major questions in prostate cancer treatment today. First, is triple therapy going to be the new standard of care for hormone-naïve metastatic prostate cancer? Second, should abiraterone plus prednisone be combined with a poly (ADP-ribose) polymerase (PARP) inhibitor for treatment of metastatic castration resistant prostate cancer (mCRPC)?
GU Oncology Now: Were any data presented about triple therapy that you consider practice-changing?
Dr Marshall: Yes. The results of the ARASENS trial indicated that triple therapy with androgen deprivation therapy (ADT) plus docetaxel plus darolutamide should be the new standard treatment option.1,2 ARASENS was a phase 3, randomized, placebo-controlled trial in 1,306 men with metastatic hormone-sensitive prostate cancer (mHSPC) randomized to receive ADT and docetaxel plus either darolutamide or placebo. After a median follow-up of 3.5 years, the risk of death in the darolutamide group was 32.5% lower than in the placebo group. Patients taking darolutamide also experienced a longer time to develop CRPC and the need for other anticancer therapies. The rates of adverse events were similar in both treatment groups.
Based on this, I would say that adding darolutamide in patients who are candidates for docetaxel in the metastatic hormone-naïve setting does seem to have a significant benefit. But what ARASENS did not answer is whether triplet therapy is warranted for patients who were being considered for doublet therapy with ADT plus a novel hormonal agent. Based on this trial, I would not switch to ADT plus darolutamide plus docetaxel in those patients. The ARASENS regimen is appropriate only for the patients who would have been selected to receive chemotherapy in the first place.
GU Oncology Now: The PRESIDE trial also investigated triplet therapy, but in a different patient population?
Dr Marshall: PRESIDE enrolled 271 men with mCRPC whose disease progressed on enzalutamide plus ADT. Men were randomized either to continue enzalutamide or to switch to placebo.3 The study found that men who continued on enzalutamide had a significant increase in progression-free survival (PFS) compared with the placebo group (median 9.53 months vs 8.28 months). So this was only a 1-month improvement in PFS. So I do not think this is really practice changing, although it may be appropriate in a few patients.
GU Oncology Now: Data were presented from two Phase 3 trials that evaluated the addition of a PARP inhibitor to abiraterone as first-line in mCRPC. What conclusions did you reach from these?
Dr Marshall: PROpel investigated the addition of olaparib vs placebo to abiraterone plus prednisone as first–line treatment in men with mCRPC that had progressed on ADT alone4 in men with and without homologous recombination repair (HRR) gene alterations. MAGNITUDE found no benefit with addition of niraparib to abiraterone plus prednisone as first-line treatment of mCRPC in men without HRR gene alterations, but did show benefit in those with HRR gene alterations.5
There were some differences between the trials in study design, doses of medications, and how the outcome was assessed. We know from other prospective and retrospective studies that disease response to PARPs can vary based on the gene alterations found in the tumor.6 So, for example, men with cancers with ataxia telangiectasia mutated (ATM) mutations do not get as much clinical benefit from PARP inhibitors compared with men with BRCA2-altered cancers. 7 So I believe that these studies highlight the necessity for early somatic and germline testing in men with metastatic prostate cancer, and that for men who are eligible for a PARP inhibitor, it is reasonable to combine a PARP inhibitor with abiraterone and prednisone.
There are insufficient data, especially given the conflicting results of the PROpel and MAGNITUDE trials, to support using PARP inhibitors in men who do not have these mutations and would not otherwise be on a PARP inhibitor. I look forward to seeing more of the results from these trials though to better understand what it means for men who do not have HRR mutated cancers.
- Smith MR, Hussain MHA, Saad F, et al. Overall survival with darolutamide versus placebo in combination with androgen-deprivation therapy and docetaxel for metastatic hormone-sensitive prostate cancer in the phase 3 ARASENS trial. J Clin Oncol. 2022;40(6 suppl):Abstract 13. DOI: 1200/JCO.2022.40.6_suppl.013
- Smith MR, Hussain M, Saad F, et a; for the ARASENS Trial Investigators. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med. Published online February 17, 2022. DOI: 1056/NEJMoa2119115
- Merseburger AS, Attard G, Boysen G, et al. A randomized, double-blind, placebo (PBO)-controlled, phase 3b study of the efficacy and safety of continuing enzalutamide (ENZA) in chemotherapy-naïve, metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with docetaxel (DOC) plus prednisolone (PDN) who have progressed on ENZA: PRESIDE. J Clin Oncol. 2022;40(6 suppl):Abstract 15. DOI: 1200/JCO.2022.40.6_suppl.015
- Saad F, Armstrong AJ, Thiery-Vuillemin A, et al. PROpel: Phase III trial of olaparib (ola) and abiraterone (abi) versus placebo (pbo) and abi as first-line (1L) therapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2022;40(6 suppl):Abstract 11. DOI: 1200/JCO.2022.40.6_suppl.011
- Chi KN, Rathkopf DE, Smith MR, et al. Phase 3 MAGNITUDE study: First results of niraparib (NIRA) with abiraterone acetate and prednisone (AAP) as first-line therapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with and without homologous recombination repair (HRR) gene alterations. J Clin Oncol. 2022;40(6 suppl):Abstract 12. DOI: 1200/JCO.2022.40.6_suppl.012
- Teyssonneau O, Margot H, Cabart M, et al. Prostate cancer and PARP inhibitors: progress and challenges. J Hematol Oncol. 2021;14(1):51. DOI: 1186/s13045-021-01061-x
- Marshall CH, Sokolova AO, McNatty AL, et al. Differential Response to Olaparib Treatment Among Men with Metastatic Castration-resistant Prostate Cancer Harboring BRCA1 or BRCA2 Versus ATM Mutations. Eur Urol. 2019;76(4):452–458. DOI: 10.1016/j.eururo.2019.02.002