ASCO 2019 Updates for ROYAL

How to Sequence Taxotere, Jevtana, Xtandi, and Zytiga

By Mark Scholz, MD

Since the advent of effective second-generation hormonal therapies such as Zytiga or Xtandi, prostate cancer experts have been wondering how these new agents should be sequenced in relation to chemotherapy. Or if they should they be given in combination. Some of the pertinent studies presented at the 2019 annual meeting of the American Society of Clinical Oncology (ASCO) aim to answer these questions. 

The first study (abstract #5000) evaluated the efficacy of Xtandi compared to Casodex in 1,125 men with newly-diagnosed metastatic prostate cancer who were still hormone sensitive. In the study, Xtandi (plus Lupron) showed longer survival compared to Casodex (plus Lupron). The biggest advantage for Xtandi was seen in men who had a lower number of metastases. This confirms a common and repeating theme: treatment initiated at an earlier stage enhances the anticancer effects of therapy on survival. This study also looked at Xtandi’s impact on survival when it was used in combination with chemotherapy (Taxotere). The study still found that Xtandi led to higher survival rates over Casodex-treated men (who also received Taxotere). However, when Xtandi and Casodex were used in combination with Taxotere, the difference in survival between the two groups was minimized, but not completely eliminated. 

In another report evaluating the effects of combining Taxotere and Xtandi (Abstract #5050) 246 ROYAL-stage men were given 8 cycles of Taxotere.  Half of the men also were treated with Xtandi.   Six months after starting therapy, the men receiving both agents had an 11% rate of disease progression compared to a 17% rate in the men treated with Taxotere alone. In the men treated with both agents, 92% had a PSA response (a decline of PSA more than 50%).  In the strictly Taxotere group, only 69% reported a PSA decline greater than 50%. Median survival was 13% longer in the men receiving the combination of Taxotere and Xtandi.

Another study looked at the “sequencing” of these agents.  In abstract # 5003, a group of 95 men with progressive hormone-resistant metastatic prostate cancer were randomly assigned to Cabazitaxel chemotherapy or to second generation hormonal therapy (either Xtandi or Zytiga).  In this study the men were characterized as having “very advanced disease.” For example, one out of five men had liver metastases and half of the men had previously undergone treatment with Taxotere chemotherapy. The study indicated that in this group of 95 men with very advanced prostate cancer, starting with Cabazitaxel resulted in longer survival than starting with Xtandi or Zytiga.

What about comparing the two types of chemotherapy available, Taxotere and Jevtana? Previous studies have shown no difference in survival rates between Taxotere and Jevtana (one such study is called “Firstana”). However, an unanswered question is whether these agents are equivalent in terms of side effects. In Abstract #5017, 195 men were randomly allocated to 4 cycles of Taxotere followed by 4 cycles of Jevtana or the opposite sequence, i.e., 4 cycles of Jevtana followed by 4 cycles of Taxotere.  Therefore, all 195 men experienced both types of chemotherapy and could be questioned as to whether one or the other subjectively showed fewer side effects.  43% of the men reported a preference for Jevtana, 27% preferred Taxotere and 30% felt there was no difference. In those describing a difference, reduced fatigue and less hair loss were the types of side effects most commonly cited.

Other than chemotherapy, there are limited options for men whose cancer progresses after being on Zytiga. Multiple studies have reported post-Zytiga PSA response rates with Xtandi are very low, in the range of 10%. Preliminary studies of Keytruda, an immunotherapy that is FDA approved for cancer of the bladder and lung, show about a 15% response rate. Since both Xtandi and Keytruda have relatively modest side effects it is reasonable to consider using them in combination.  In Abstract #5010, 69 men progressing on Zytiga were treated with a combination of Xtandi plus Keytruda. They reported that 27% of the men responded with a greater than 50% decline in PSA suggesting some efficacy for this combination.

In conclusion, management of ROYAL is dynamic. When utilizing active anticancer agents, close monitoring of PSA and scans is important to determine if the treatment is working.  When treatment is ineffective, it must be stopped and another type of therapy promptly initiated.

The studies cited above suggest that men with advanced metastatic disease should be treated with chemotherapy first, perhaps in combination with Xtandi or Zytiga.  When deciding which of the two types of chemotherapy to use—Taxotere or Jevtana—it appears that more men prefer Jevtana. A combination of Keytruda and Xtandi may be a viable option for men with disease progression on Zytiga.  The above studies show hope for men with ROYAL stage prostate cancer. Always keep in mind that secondary treatment is most effective if started at the very first sign of hormone resistance. 

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