Androgen-deprivation therapy has been, and remains, the standard of care for patients with metastatic prostate cancer. Patients are often surprised to learn that was all we would do to control their disease and sometimes asked why they would not receive chemotherapy, as for other cancers. I would take the time to say that, although it would appear to make sense, we did not have the evidence it should be used before they became resistant to androgen-deprivation therapy. I have to admit this was frustrating, since it actually made a lot of sense that if we hit harder, we might better control the disease before all of the resistance mechanisms set in. This is especially true when we see the relatively modest results obtained with docetaxel in the castration-resistant prostate cancer setting.1
CHAARTED and LATITUDE Trials: Pleasant Surprises
The paradigm changed in 2014 with the results of the CHAARTED trial, which showed significantly improved survival in patients with metastatic castration-sensitive prostate cancer to a much greater extent than when used in castration-resistant prostate cancer.2 However, the benefit appeared to be limited to those with high-volume disease.
Fred Saad, MD, FRCS
The next pleasant surprise was when the abiraterone data were reported in the LATITUDE trial, which demonstrated a survival advantage in the high-risk metastatic castration-sensitive prostate cancer population.3 Although the combination of androgen-deprivation therapy with another agent having a different mechanism of action made sense, the thought that intensifying hormonal therapy would lead to such improvements in survival was intriguing. The LATITUDE data helped consolidate the theory that earlier intervention with a hormonally based approach leads to a more profound initial response and longer time to resistance and disease progression, with all this leading to improved survival.
We already had suggestions from metastatic castration-resistant prostate cancer trials that the response and survival advantages with the hormonally based therapies appeared to be more pronounced in patients with a lower tumor burden (ie, lower prostate-specific antigen [PSA] levels, less pain, and fewer sites of metastases). This could be explained by the idea that with a lower tumor volume, there may be fewer hormone--insensitive clones that would be unresponsive to an androgen receptor signaling/targeted inhibitor.
Given the results of the CHAARTED and LATITUDE trials, the general consensus was, however, to limit the use of either docetaxel or abiraterone to patients with newly diagnosed high-volume or high-risk metastatic castration-sensitive prostate cancer. Patients again questioned why we were reluctant to intensify treatment in lower-risk patients and in those whose disease progressed from a localized to metastatic state. Again, the lack of convincing data prevented us from doing things that actually made sense. The next best thing was to use a sequential approach of androgen-deprivation therapy, with introduction of agents such as abiraterone or enzalutamide when metastatic castration-resistant prostate cancer appeared.4,5 However, the real-world setting often results in delays or even nonuse of life-prolonging therapies when patients transition from metastatic castration-sensitive to metastatic castration-resistant prostate cancer.
From SPARTAN to TITAN: Welcome Results
The TITAN trial was one of the first studies to specifically target the low-risk metastatic castration-sensitive prostate cancer patient population.6 The study used apalutamide, which had previously been shown in phase II evaluation to be effective in castration-resistant prostate cancer and eventually was assessed in the phase III SPARTAN study in high-risk nonmetastatic castration-resistant prostate cancer.7
The SPARTAN study showed a 2-year delay in metastasis-free survival, and apalutamide became the first agent to be approved for use based on this novel endpoint in prostate cancer. The study actually added to the evidence that a lower tumor burden leads to better outcome based on the prolonged (> 40 months) time to PSA progression. Given there are so many agents available in the metastatic castration-resistant prostate cancer setting, it was believed that overall survival endpoints would no longer be attainable. It was, however, reassuring that radiographic progression-free survival would become an acceptable endpoint for new drug approval.
With this in mind, the results of the TITAN trial were surprising and very much welcome. The results were surprising in that apalutamide was not only able to delay disease progression, but also to significantly improve overall survival in men with the whole spectrum of metastatic castration-sensitive prostate cancer. Also surprising was how quickly this difference in overall survival was demonstrated. It is important to note that patients were well managed, and sequential therapy was appropriately used. The results strongly suggest that early aggressive therapy in all patients with metastatic castration--sensitive prostate cancer is more effective than sequential treatment. With a median time to castration-resistant prostate cancer in the patient with metastatic disease of only 1 year, the added burden of treatment to the patient, as well as to the health-care system, appears well worth the cost.
Another revealing aspect of the TITAN trial is the survival benefit appeared to be at least as good in patients with low-volume disease as in those with high-volume disease, and regardless of whether the patient was newly diagnosed or had disease progression from a localized to a metastatic state. Although we always prefer not to read too much into subsets, it is important to note that those with combined visceral and bone metastases do not do as well. Whether they would have done better with chemotherapy or some other approach is unknown, but clearly these patients require particular attention. Obviously, quality of life remains central for patients with metastatic disease, so it was reassuring that quality of life was maintained even with the addition of apalutamide.
From Rags to Riches
Similar to what we experienced in metastatic castration-resistant prostate cancer, we are now going from rags to riches in metastatic castration-sensitive prostate cancer with four effective agents, as well as finding that treatment is relevant in low-volume metastatic castration-sensitive prostate cancer. The objective should now be to aim for the best response upfront.
For high-volume/high-risk metastatic castration-sensitive prostate cancer, we now have several effective agents available, and deciding which to use will include tumor/patient characteristics, cost, and our personal biases/preference as physicians. Androgen-deprivation therapy alone appears to be suboptimal care in 2019. For patients who do not have high-volume or high-risk disease (I have never liked using “low-risk” to describe a lethal disease), there will still be controversy around the upfront use of apalutamide or enzalutamide8 in all patients vs waiting until metastatic castration-resistant prostate cancer to introduce subsequent therapy.
We all look toward continued research in predicting tumor response/resistance in individual patients. Until then, my personal recommendation for those who decide to start androgen-deprivation therapy alone as systemic therapy in metastatic castration-sensitive prostate cancer would be to observe PSA response closely and consider additional treatment if PSA levels do not decline to less than 0.2 ng/mL after 6 to 8 months. Such patients are most likely to have early progression to metastatic castration-resistant prostate cancer and shortened survival with androgen-deprivation therapy alone. In the end, shared decision-making with patients about the pros and cons of intensifying therapy in metastatic hormone-sensitive prostate cancer remains critical.
Dr. Saad is Professor and Chief of Urology; Director of GU Oncology; and Raymond Garneau Chair in Prostate Cancer, University of Montreal Hospital Center.
DISCLOSURE: Dr. Saad has received honoraria as a consultant and received institutional research funding from Astellas, AstraZeneca, Bayer, Janssen, and Sanofi.
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8. Davis ID, Martin AJ, Stockler MR, et al: Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med 381:121-131, 2019.