Optimal Sequencing of Cancer Treatments an Increasingly Important Question

JHOP - August 2022 Vol 12, No 4 - Editorial
Scott A. Soefje, PharmD, MBA, BCOP, FCCP, FHOPA
Director, Pharmacy Cancer Care, Mayo Clinic, Rochester, MN
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When pharmacists think of chemotherapy sequencing, we are usually considering which order to give the specific chemotherapy agent within the current treatment plan. However, as more treatments become available for cancer, one of the questions that needs to be answered is—What is the appropriate sequencing of therapies, if any, when multiple therapies are available?

Most likely, we will not see head-to-head clinical trials conducted to answer this question.1 Therefore, real-world clinical trials will be the path to answering complex questions such as this, and this is especially important in oncology areas that are seeing a rapid expansion of treatment options at a time of limited or reduced resources.2 Real-world data also become important when we start treating patients who are different from the patient population that was enrolled in the clinical trials that led to a drug’s approval by the US Food and Drug Administration.2

Real-world data related to tumor types such as lung cancer, colorectal cancer, and melanoma, have shown that the sequencing of drug therapies may affect the overall outcomes of patients.3-5 Prostate cancer is another area that has a growing body of evidence to support the idea that the sequencing of drug therapies is important.6,7

In this issue of the Journal of Hematology Oncology Pharmacy, Newman and colleagues add to the evidence on the sequencing of treatments for prostate cancer.8 In their retrospective chart review, Newman and colleagues analyze real-world data on the effect of sequencing abiraterone followed by enzalutamide or enzalutamide followed by abiraterone for patients with castration-resistant prostate cancer (CRPC) at the VA Northeast Ohio Healthcare System. Newman and colleagues examined patients who had received abiraterone and enzalutamide in sequence during the study period, without receiving any other drug therapies between these 2 drugs.8

The outcomes that were measured in the study included the combined prostate-specific antigen (PSA) and progression-free survival (PFS), which was defined as the total time from the start of the first therapy with abiraterone or enzalutamide until the PSA progression with the second drug therapy of abiraterone or enzalutamide. The secondary outcomes included combined radiographic PFS and overall survival (OS).8

Of the 77 patients who met all the study inclusion criteria, only 57 had a combined PSA-PFS that could be evaluated across the 2 drug sequences. The abiraterone-before-enzalutamide group had a longer difference in combined PSA-PFS than the enzalutamide-before-abiraterone group (hazard ratio, 0.46; 95% confidence interval, 0.26-0.83). This resulted in a 7.1-month increase in PSA-PFS. The difference in PSA-PFS significantly favored the use of abiraterone first in the sequence.8

Although longer in the abiraterone-first group, the radiographic PFS and OS outcomes did not significantly differ between the groups. Newman and colleagues did account for adherence through the medication possession ratios and the discontinuation of a drug because of adverse events, with the results showing no significant differences between the 2 groups based on either sequence.8

The results of this study demonstrate that using real-world data can add to the growing body of evidence to answer a specific clinical practice question.8 This study is consistent with other studies that have examined the same chemotherapy sequencing question in patients with prostate cancer, and its results provide further evidence to support the finding that abiraterone given before enzalutamide produces better outcomes than the reverse sequence.6,7

The next step is to determine the best overall treatment sequence in patients with CRPC. This sequencing determination also needs to consider the specific chemotherapy agents used; for example, one study suggested that docetaxel given before the use of a second-generation androgen deprivation therapy (or androgen receptor inhibitors) is more effective than the reverse sequence.6 The final step should be to add the value component, to look at the cost-effectiveness of using different sequences of therapies.

Growing evidence shows that the sequencing of therapies may affect the overall outcomes of patients with CRPC, and because androgen receptor inhibitors, such as abiraterone and enzalutamide, are used earlier in the treatment of patients with CRPC, the need for optimal sequencing is becoming increasingly important.8 The current evidence-based guidelines, however, do not outline the appropriate sequencing of agents in the treatment of prostate cancer.9

Advances in cancer therapies are providing significant improvements in patient outcomes, but are also raising new questions about the best sequencing of these treatments.2 Given the lack of head-to-head clinical trials to help answer our questions, real-world evidence will play an important role in examining the effects of treatment sequencing and how we ultimately develop guidelines or pathways to reflect such knowledge.1

The study by Newman and colleagues is a great addition to the growing body of evidence of the importance of determining the optimal sequencing of chemotherapy in prostate cancer. Oncology pharmacists need to start to consider sequencing as the chemotherapy is given, both within an individual regimen as well as in terms of the broader picture of the overall sequencing regimens, to improve patient outcomes.


  1. Khozin S, Blumenthal GM, Pazdur R. Real-world data for clinical evidence generation in oncology. J Natl Cancer Inst. 2017;109:187. doi: 10.1093/JNCI/DJX187.
  2. Caffo O. Treatment sequencing in oncology: balancing clinical trial and real-world evidence. Future Oncol. 2019;15:2887-2889.
  3. Girard N. Optimizing outcomes and treatment sequences in EGFR mutation-positive non-small-cell lung cancer: recent updates. Future Oncol. 2019;15:2983-2997.
  4. Luke JJ, Ghate SR, Kish J, et al. Targeted agents or immuno-oncology therapies as first-line therapy for BRAF-mutated metastatic melanoma: a real-world study. Future Oncol. 2019;15:2933-2942.
  5. Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004;22:229-237.
  6. Andrews JR, Ahmed ME, Karnes RJ, et al. Systemic treatment for metastatic castrate resistant prostate cancer: does sequence matter? Prostate. 2020; 80:399-406.
  7. Caffo O, Maines F, Kinspergher S, et al. Sequencing strategies in the new treatment landscape of prostate cancer. Future Oncol. 2019;15:2967-2982.
  8. Newman NJ, Gordon SE, Nock CJ, et al. Comparing the impact of abiraterone and enzalutamide sequencing on progression-free survival in veterans with metastatic castration-resistant prostate cancer. J Hematol Oncol Pharm. 2022;12(4):180-187.
  9. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Prostate Cancer. Version 4.2022. May 10, 2022. www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed July 21, 2022.
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