Apalutamide Drives Ultra-Low PSA Levels in mCSPC
In an interview with Targeted Oncology, Neeraj Agarwal, MD, discussed findings from the TITAN trial which were presented at ESMO 2023.
Neeraj Agarwal, MD
In the TITAN study (NCT02489318), more patients with metastatic castration-sensitive prostate cancer (mCSPC) achieved ultra-low prostate-specific antigen (PSA) values when given apalutamide (Erleada) vs placebo. Regardless of disease volume, these rapid and deep ultra-low PSA values correlated with significantly improved survival outcomes among patients.1
The analysis included 525 and 527 patients who were given 240 mg of apalutamide or placebo plus androgen deprivation therapy (ADT) daily, and 2 groups of ultra-low PSA were assessed, including >0.02 to ≤0.2 ng/mL and ≤0.02 ng/mL. Investigators sought to evaluate the groups association with overall survival, radiographic progression-free survival, time to castration resistance, and time to PSA progression.
There were 515 patients given apalutamide and 520 patients given placebo who had evaluable ultra-low PSA values and among them, 49% and 17% achieved ≤0.02 ng/mL PSA during the study, respectively. By 3 months, the 2 levels, >0.02 to ≤0.2 ng/mL and ≤0.02 ng/mL, were achieved in 38% and 23% of patients given apalutamide and 15% and 5% of those given placebo. At 6 months, these values were 29% and 36%, and 17% and 6% for apalutamide and placebo.
At 3 or 6 months, patients with >0.02 to ≤0.2 ng/mL and ≤0.02 ng/mL PSA values had improved long-term outcomes irrespective of volume, and volume-adjusted outcomes were also significantly improved. Moreover, the safety profile of apalutamide was consistent with what has previously been reported across subgroups.
In an interview with Targeted OncologyTM, Neeraj Agarwal, MD, director of genitourinary oncology program and professor of medicine at the Huntsman Cancer Institute, University of Utah, discussed findings from the TITAN trial which were presented at the 2023 European Society of Medical Oncology (ESMO) Annual Meeting.
Targeted Oncology: Can you provide a brief overview of the TITAN trial?
Agarwal: TITAN was a phase 3 trial which led to approval of apalutamide for our patients with metastatic hormone-sensitive or castration-sensitive prostate cancer. The TITAN study was a large study of more than 1000 patients who had a new diagnosis of metastatic hormone-sensitive prostate cancer. They were randomized to the standard of care androgen deprivation therapy plus or minus apalutamide. The control arm was ADT plus placebo, and the experimental arm was ADT plus apalutamide, which is a androgen receptor pathway inhibitor. Radiographic progression-free survival and overall survival were the dual primary end points. At the first interim analysis of this trial, after a median follow-up of approximately 23 months, the trial met the primary end point and both these dual primary end points. There was a 35% reduction in risk of death and about 50% reduction in risk of progression or death. Both overall survival and radiographic progression-free survival were improved in a statistically significant and clinically meaningful fashion.
More importantly, we looked at these patients with a longer follow-up. After the first interim analysis, when overall survival was positive, patients on the placebo arm were allowed to cross over to the apalutamide, and 40% of patients crossed over after having received treatment for variable duration. We all know that when placebo patients or control arm patients get crossed over to the experimental arm, that definitely attenuates overall survival. Using standard statistical tools, which are well validated, we looked at what would have happened to overall survival had these patients on the placebo group not been crossed over to the experimental arm. We found overall survival to be even more striking. There was a 50% reduction in risk of death, if you account for the crossover. These data are very compelling. These data establish apalutamide as a very effective option for our patients with newly diagnosed metastatic hormone-sensitive prostate cancer.
We also reported quality-of-life data as reported by the patients themselves. Patient-reported outcomes and health-related quality-of-life were well maintained while the patients were living longer. Patients were living much longer without compromising quality-of-life when treated with apalutamide. This is a very meaningful end point for our patients who are contemplating whether they should get only androgen deprivation therapy, which is no longer a standard of care. Unfortunately, many patients out there in the community are still getting ADT monotherapy. For those patients, I would like to re-emphasize that quality-of-life is not compromised while our patients are living much longer with apalutamide.
Conceptual image for prostate cancer treatment, 3D illustration showing destruction of a tumor inside prostate gland: © Dr_Microbe - stock.adobe.com
Could you further discuss the key findings from the trial and the subsequent analysis regarding the use of apalutamide in the space?
At ESMO, we presented the data on PSA response, and how it correlates with survival. Taking a step back, we wanted to look at the degree of PSA response and its effect on overall survival for 2 reasons. Number 1, we have seen in many practices across the United States and across the world that many patients are receiving androgen deprivation therapy monotherapy for newly diagnosed metastatic hormone-sensitive prostate cancer. The reasons we have seen are that PSA is going down, so why do we need to intensify treatment? In this context, there was another study reported in 2007 in the context of ADT monotherapy data that patients who experienced a PSA of 0.2 ng/mL or less were living much longer than patients who are not able to experience a PSA level of 0.2 ng/mL. We decided to look at the relevance or impact of very low PSA levels, less than 0.2 ng/mL, and then even further lower values of 0.02 ng/mL and how it impacts overall survival and should we be satisfied with a 50% decline in the PSA level. PSA level at baseline was 100. Should we be satisfied with a PSA level of 50 ng/mL with ADT monotherapy or should we strive to achieve a PSA level of 0.2 ng/mL or even deeper PSA levels for our patients?
In this context, we looked at the PSA values and data of these patients who were treated with apalutamide, and we saw striking results. If PSA levels were 0.2 or less within 3 months of the treatment with apalutamide, there was a much remarkable reduction in risk of death vs in patients who did not experience a PSA of level of 0.2 or less. This was at 54% reduction in risk of death. If PSA came down to 0.2 or less, then we looked at PSA of 0.02 ng, even further decline in the PSA level. The majority of patients are able to experience a PSA of 0.2 or less within 3 months. If you extend this period to 6 months, we are talking about more than 60% of patients getting to the PSA level of 0.2 ng/mL or less. I want to repeat there was a 54% reduction in risk of death when PSA level went down to less than 0.02.
Now if you look at 0.02 ng/mL, if my patient is able to experience a PSA of 0.02 ng/mL or less, this is approximately an 80% reduction in risk of death. Interestingly, how fast PSA goes down also matters. If PSA goes down to less than 0.02 ng/mL within the first 3 to 6 months, there was close to 85% reduction in risk of death.
What is the meaning of these data?
First of all, I love to hear about an 80% reduction in risk of death for my patients. It makes me so optimistic when I'm treating my patients. Same applies to my patients. We give them hope and give them time with their families without compromising quality-of-life to live longer. My conclusion based on these data is that we can no longer be satisfied with a PSA with a decline of 50% with ADT monotherapy. We should all strive to achieve a PSA level of less than 0.2 or if possible less than 0.02 ng/mL for our patients, which will allow them to live much longer on apalutamide therapy without compromising their quality-of-life.
Are there any other survival data or end points that you could highlight?
There are so many other clinically meaningful end points. When we improve overall survival, we often forget about time to castrate-resistant prostate cancer, which is the painful state of prostate cancer, time to PSA progression, and that is nerve racking for my patients to see PSA going up. PSA progression occurs usually earlier than scan progression, and that usually makes my patients very anxious when they experience PSA progression. Time to chemotherapy for example, is a relevant end point. Yes, we all are looking at overall survival because that is a regulatory end point for drug approval, and radiographic progression-free survival is another regulatory end point, but time to CRPC, time to chemotherapy, time to PSA progression are also very meaningful end points.
All of those end points were delayed when we were using apalutamide, and all those end points were further delayed when my patients were able to experience a PSA of 0.2 or less than 0.02. I'm so glad you asked me that question about what other end points there are because these are the clinically meaningful end points, which are also improved significantly, both clinically and statistically, when my patients are on apalutamide and when they are able to experience a PSA of less than 0.02.
The study mentioned the crossover rate from the placebo arm to the treatment arm. How might that affect the interpretation of the trial results?
Patients who crossed over from placebo arm to apalutamide arm after a variable duration of time had improved overall survival. If you carefully look at the overall survival curve, their survival was not at the level when patients were treated with apalutamide from the time of diagnosis. There are 2 critical data points, which are practice relevant. Number 1,
patients should be starting apalutamide earlier. They cannot wait for suboptimal PSA response after 1 or 2 years without disease progression, they should be starting apalutamide early on based on these results, because patients who had the best survival outcomes were the ones who started apalutamide from day 1. Yes, survival outcomes were also improved in patients who switched over from the placebo to the apalutamide arm after a variable duration of time, usually 1 to 2 years. That basically tells me apalutamide remains effective, but it is most effective when started early on.
Number 2, if you account for the crossover, this survival benefit actually improves the hazard ratio from 0.35 to 0.50. Risk reduction improved with apalutamide. Based on all these data from the TITAN trial, our conclusion is that early use of apalutamide remains the key.
We should no longer be satisfied with a 50% decline of the PSA or 90% decline in the PSA. We should be striving to achieve a PSA of 0.02 and if possible 0.02. So 0.2 is another value and then 0.02 is an even deeper PSA level, because each one of those values basically means further improved survival, further improved time to castration resistance, further delay of chemotherapy, and further improvement time to PSA progression without compromising quality-of-life.
Are there any next steps for this research?
The next step is obviously for patients who are not experiencing a PSA of 0.2 or less.
How can we understand these patients, which are fortunately a minority of patients. There are patients who are not experiencing optimal PSA response and it means we need to do something more for those patients. Further, escalation of treatment without waiting for onset of castration-resistant prostate cancer, without waiting for radiographic progression, [determining if we can] do something for these patients within 6 months or after 6 months when they are not experiencing a PSA of 0.2 [is needed]. We should be doing something more for them. Fortunately, trials are being developed in those settings.
The opposite is also true of patients who are doing well. They are experiencing a PSA of 0.2 ng/mL, are living for years and much longer than what we have ever experienced. To minimize the long-term toxicities, we should be working on measures such as exercise programs, diet programs, and other survivorship issues. These are way more important for our patients with metastatic prostate cancer who are experiencing a PSA of 0.2 ng/mL. Within 6 months, we ought to be talking to them about survivorship issues more often than ever, [as well as] cardiovascular issues, how to keep them healthier, and how to make sure they are surviving. They continue to survive for a decade or longer. Their quality-of-life is not being compromised by muscle loss or bone loss, so it's a good problem to have.
The last thing I would like to highlight is that we have started a de-escalation trial in this setting, sponsored by Janssen. Patients who experience a PSA of 0.2 ng/mL in the first 6 months after starting ADT plus apalutamide will have the opportunity to drop the castration part. Patients will be randomized to ADT plus apalutamide, which is continuation of the standard therapy vs apalutamide only, and we drop the castration therapy. I hope that will further improve quality-of-life for those patients, while keeping them alive for much longer. Those are the next steps in my view
