Pharmaceutical companies have greatly expanded the drug armamentarium for treating metastatic castration-resistant prostate cancer (mCRPC) in the past decade. Medical researchers have been exploring how best to use these medications, notably the sequence in which patients should receive the drugs to experience the best outcomes. They appear to be making progress.

“Optimal treatment sequencing is really starting to come into focus for patients with mCRPC,” Benjamin Maughan, MD, PharmD, Assistant Professor of Genitourinary Medical Oncology at the Huntsman Cancer Institute of the University of Utah in Salt Lake City, told Renal & Urology News. “There seems to be 2 separate types of differentiating factors: clinical parameters and molecular parameters that are guiding treatment sequencing.”

For instance, in the prospective randomized CARD trial, which was published recently in the New England Journal of Medicine, Dr Maughan noted that the clinical factor of “short-term duration of clinical benefit” from first novel hormone therapy (NHT) determined that the sequence of NHT (abiraterone or enzalutamide)-taxane (cabazitaxel) is superior to an NHT-NHT sequence. The PROfound trial presented at the European Society for Medical Oncology (ESMO) 2019 congress is a good example of a study using molecular features to clarify optimal sequencing, Dr Maughan said. The trial showed that a sequence of NHT (abiraterone or enzalutamide) followed by olaparib, an inhibitor of poly-ADP ribose polymerase (PARP), an enzyme involved in DNA repair, was superior to a sequence of NHT-NHT in patients with DNA repair deficits, particularly BRCA1 and BRCA2 genomic alterations. Other sequences need to be explored, he said, but the optimal sequences for hormone therapies and chemotherapies are becoming clearer, Dr Maughan said.

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In another presentation at the ESMO 2019 congress, Carlo Cattrini, MD, of the Prostate Cancer Clinical Research Unit, Spanish National Cancer Research Centre in Madrid, and colleagues reported findings from the PROREPAIR-B study demonstrating significantly longer progression-free survival among men with mCRPC who received abiraterone or enzalutamide upfront compared with those who received first-line docetaxel (10.8 vs 8.3 months). Overall survival (OS) between the treatment sequences, however, did not differ significantly (31.3 vs 29.9 months, respectively).

At the Society of Urologic Oncology’s 20th annual meeting this past December in Washington, DC, Jack R. Andrews, MD, and colleagues at Mayo Clinic in Rochester, Minnesota, reported on a study demonstrating that upfront chemotherapy with docetaxel for mCRPC followed by second-generation androgen deprivation therapy (ADT) with abiraterone or enzalutamide if chemotherapy fails is associated with superior cancer-specific and overall survival compared with the opposite treatment sequence. Data indicate that the sequence of systemic therapy may influence outcomes for mCRPC, and docetaxel should be considered prior to second-generation ADT, the investigators concluded.

In a 2019 paper published in Lancet Oncology, a team led by Kim N. Chi, MD, of the Vancouver Prostate Centre in Vancouver, British Columbia, reported on a phase 2 randomized trial showing that men with newly diagnosed mCRPC experience slower PSA progression if they receive abiraterone plus prednisone first followed by enzalutamide rather than the reverse sequence. “Our trial is the first, to our knowledge, to show an advantage to using a sequencing strategy of both drugs: the treatment sequence of abiraterone plus prednisone followed by enzalutamide had a longer time to PSA progression than did the opposite sequence,” Dr Chi and colleagues wrote.

Some studies, however, have not found a difference in mCRPC drug sequencing. In a retrospective study of treatment sequences in real-world practice published in Clinical Genitourinary Cancer in 2019, Kazutaka Okita, MD, of Hirosaki University School of Medicine in Hirosaki, Japan, and colleagues found no significant difference in OS among men with mCRPC treated with abiraterone first followed by enzalutamide, or the reverse sequence, abiraterone or enzalutamide first followed by docetaxel, or the reverse sequence, or docetaxel first followed by cabazitaxel.

In Dr Maughan’s view, sufficient evidence exists to include mCRPC treatment sequences in clinical practice guidelines based on both molecular and clinical characteristics. “However, these guidelines should take into consideration the quality of the evidence,” Dr Maughan said. “I believe that the guidelines should provide a general guide but leave flexibility to allow the providing clinician to use any sequence. The data to date are not strong enough to endorse a single, specific sequence as the only option that should be considered for any given patient.”

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De Wit R, de Bono J, Sternberg CN, et al. Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer. N Engl J Med. 2019;381:2506-2518. doi: 10.1056/NEJMoa1911206

Khalaf DJ, Annala M, Taavitsainen S, et al. Optimal sequencing of enzalutamide and abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label phase 2, crossover trialLancet Oncol. 2019;20:1730-1739.

Cattrini C, Romero-Laorden N, Castro E, et al. Impact of treatment sequence in patients in metastatic castration-resistant prostate cancer (mCRPC): data from the prospective PROREPAIR-B study. Presented at the European Society for Medical Oncology 2019 Congress held September 30 to October 1 in Barcelona, Spain. Poster 880P

Andrews J, Ahmed M, Karnes R, et al. Systemic treatment for metastatic castration resistant prostate cancer (m-CRPC): Does sequence matter? Presented at the 20th annual meeting of the Society of Urologic Oncology 20th Annual Meeting held December 4 to 6 in Washington, DC. Poster 73.