(1) Give Taxotere (docetaxel) First
In a retrospective study presented at the Society for Urologic Oncology 2020 meeting, researchers from the Mayo Clinic reported a small 112 patient cohort with metastatic castration-resistant prostate cancer (mCRPC). The study included two different groups:
· Group A (80 men) were given docetaxel chemotherapy (Taxotere) followed by one of the second-line hormonal therapies: either abiraterone (Zytiga) or enzalutamide (Xtandi)
· Group B (32 men) were given a second-line hormonal therapy then followed by Taxotere. It was noted that bone metastases were more common in Group B (87%) than Group A (58%)
Three-year survival was:
· cancer-specific survival: 87% Group A vs. 64% Group B
· overall survival: 82% Group A vs. 61% Group B
· these results were similar for men who had a high-volume of metastases, excluding those with lymph node-only disease
This study was not a prospective randomized clinical trial; it was a retrospective trial. However, it comes to a different conclusion than from a couple of earlier retrospective analyses.
Sonpavde et al. reported from an analysis of 1445 men at VA hospitals that there was no difference in overall survival among those who started with taxanes vs. those that began with second-line hormonal therapy.
In a study at Johns Hopkins, Maughan et al. reported no statistically significant differences in total progression-free survival related to the order in which Taxotere or Zytiga were given. Both studies adjusted for disease characteristics.
In the STAMPEDE trial of newly diagnosed men with metastatic hormone-sensitive prostate cancer (mHSPC), there was no difference in survival among men who were randomized to get Taxotere or Zytiga first (see this link). The Mayo study's difference may be due to "selection bias" in the retrospective study - Group A may have received Taxotere first because they were healthier and more likely to survive.
But even if the survival difference is an artifact of the study methodology, there are other reasons to do Taxotere first:
· Side effects are less when chemo is given earlier
· In fact, side effects are no worse for chemo or Zytiga (see this link). The differences are in the kinds of side effects, but not in their seriousness.
· By starting with six infusions of Taxotere, one can use Zytiga after only 15 weeks, but if one begins with Zytiga, it may be three years before Taxotere can be tried (see this link).
There doesn't seem to be any cross-resistance between taxanes and Zytiga (as there is between Zytiga and Xtandi). A pilot trial combined the two without finding excessive toxicity, and more extensive trials of the combination are ongoing; for example, this one.
(2) Then Give Zytiga (abiraterone) before Xtandi (enzalutamide)
Khalaf et al. reported the results of a randomized Phase 2 trial in British Columbia. Two hundred two newly diagnosed mCRPC men were randomized to either Zytiga or Xtandi first. After progressing on the first therapy, they were given the second therapy (cross-over).
· The Zytiga-first men progressed after 19 months vs. 15 months in the Xtandi-first group
· After cross-over, PSA was reduced by more than 30% in 36% of those who had Xtandi-second vs. only in 4% of those who had Zytiga-second
This trial signals that the extended progression-free time among those who use Zytiga before Xtandi will translate to extended survival.
It's worth noting that it has been found that Zytiga can work a median of 10 months longer if one switches from prednisone (10 mg/day) to dexamethasone (0.5 mg/day) when progression begins (see this link).
A trial combining Zytiga and Xtandi found no benefit to combining the two drugs, but toxicity was worse than Xtandi alone. A small trial of Zytiga monotherapy (without ADT) showed that it could reduce testosterone on its own, and another small trial suggested that the monotherapy did not compromise oncological outcomes.
(3) Then Give Jevtana (cabazitaxel) third
Jevtana is currently FDA-approved for men in whom Taxotere has already been tried and failed. Jevtana and Taxotere (both taxanes) are virtually identical in oncological results when given as first-line therapy (see this link) with a similar degree of toxicity. Suppose Taxotere and one of the second-line hormonal therapies (Zytiga or Xtandi) have already been tried. Is it better to try the other second-line hormonal therapy next, or is Jevtana a better choice for the third therapy? De Wit et al. found the answer.
They randomized patients who already had Taxotere and one of the two second-line hormonal to receive either the other second-line hormonal or Jevtana.
· 126 received Jevtana
· 58 received Zytiga
· 66 received Xtandi
After 9.2 months median follow-up,
· Imaging-based progression-free survival was 8.0 months for Jevtana vs. 3.7 months for the hormonal therapy
· The advantage of Jevtana was maintained regardless of risk characteristics and treatment history
· The benefit for Jevtana was confirmed despite to which hormonal therapy it was compared.
· Overall survival was 13.6 months for Jevtana vs. 11.0 months for hormonal treatments.
· PSA was reduced by at least 50% in 36% of men using Jevtana vs. 14% using hormonal treatments.
· Tumors shrank in 37% of men using Jevtana vs. 12% using hormonal therapies
· Serious adverse events of any grade were similar for all therapies at 39%.
· Adverse events leading to death were more frequent with the hormonal treatments (11%) than Jevtana (6%)
· Pain was improved more by Jevtana (in 45% of men) than by hormonal treatment (in 19% of men)
· Skeletal events (fractures, spinal compression) occurred more frequently among those taking hormonal treatment (51%) than Jevtana (29%)
Jevtana was at least as good or had a clear advantage on every measure of success.
(4) Then Give Xtandi fourth
There is some evidence that taxanes (like Taxotere or Jevtana) can reverse one hormonal resistance mode (AR-V7 splice variance). Research continues on methods to reverse resistance (e.g., see subsection - "what's next?"). Although there is known cross-resistance between Zytiga and Xtandi, Xtandi usually works for a while after Zytiga.
Other Medications Should Also Be Used
Other medicines approved for men with mCRPC include older anti-androgens (like bicalutamide), Xofigo, Provenge, and Keytruda (but only in the rare event of MSI-hi/dMMR). It would save time if any of these could safely be piggybacked on top of another therapy.
Older anti-androgens (like Casodex or flutamide) are still used sometimes in the mCRPC setting, mostly in combination with a GnRH agonist (like Lupron). The combination is somewhat more beneficial (see this link) than a GnRH agonist alone and provides a short-term benefit at a low cost. Sometimes, cancer learns how to feed on the anti-androgen, and removing it leads to a reduction in PSA (called anti-androgen withdrawal syndrome). Newer anti-androgens (like Xtandi) don't seem to do this.
It is unknown where the newest anti-androgens fit into sequencing. Erleada and Nubeqa have been approved for other prostate cancer indications, but not yet for mCRPC.
Xofigo cannot be prescribed after any visceral metastases have been detected. However, it does work on bone metastases. Xofigo works better when used sooner rather than later in the disease course, but a trial combining it with Zytiga was stopped early because of a high rate of skeletal events. Early results of a new trial combining Xofigo and Xtandi show that adding a bone-protective agent (Xgeva or Zometa) can ease the problem.
Provenge should be included in the treatment sequence as it has been demonstrated to extend survival. Provenge may synergize with radiotherapies or chemo because they present many cancer antigens for the amped-up immune system to tune into. There is evidence that Provenge may augment an abscopal effect (systemic immune response). Provenge seems to be more effective and should ideally be given while the PSA is low or lowered by another treatment. Other immunotherapies, which show little therapeutic promise alone, may be beneficial in combination with chemo or additional therapies. We still need studies evaluating their potential efficacy in combinations.
PARP inhibitors are recently approved for men with mCRPC who also have specific genetic mutations, both in the germline and somatic. (See Cancer ABCs chart explaining the PARP Inhibitors Approved for Prostate Cancer).
Several clinical trials are ongoing combing carboplatin with taxanes.
Lu-177-PSMA-617 and similar radiopharmaceuticals are in ongoing trials. The VISION trial used it only among men who had been pre-treated with chemo and Zytiga or Xtandi. If it gets FDA approval, it will be limited to use after those other treatments. However, trials are ongoing for earlier use and in combination therapy. There is probably an optimum time to obtain benefit from the use of PSMA-directed therapies. Combination with different PSMA-targeted radionuclides (like Ac-225) and with multiple membrane targets are being explored.
There are other potential therapies still in clinical trials. Many are pathway growth inhibitors that may work best in combinations. Therapies tailored to specific genomic mutations are in their infancy but show great future promise for prostate cancer treatment.
