ADT Vacation or Intensification? What Do We Know About Which Way To Go?

It is standard care to offer ADT to prostate cancer (PCa) patients experiencing a rising PSA after localizing prostate cancer with curative intent. Because of the many side effects of ADT, patients in consult with their oncologist need to consider not just their risk of dying from prostate cancer, but their overall health and quality of life in deciding to start on ADT.

Once they elect to go on ADT, many patients want to know how long they need to stay on that treatment. Here the decision gets more complicated, for patients are increasingly advised that for cancer control they would do better on not just basic ADT, but on an intensified ADT protocol. Those are ones where other treatments are added in, such as chemotherapy and/or an ARTA (e.g., drugs like Xtandi, Erleada or Zytiga).

Many patients on ADT are so bothered by the side effects of basic ADT that they seek intermittent therapy where they take a vacation from ADT and cycle on and off it. Indeed, several studies have shown that many patients can have comparably long-term cancer control on intermittent ADT as good as on continuous ADT. For more advanced patients, however, such intermittent treatment may not be the best strategy and intensified ADT protocols may be a better way to go.

In terms of the options, the literature can sound conflicting. For example, a recent review and meta-analysis of intermittent versus continuous ADT by Becker et al. (2023) concluded that intermittent ADT is “less likely to yield adverse side effects [and that] future treatment guidelines should consider these advantages over continuous androgen deprivation therapy.”

In contrast, a series of papers in the last six months in prestigious journals like Lancet Oncology, Journal of Clinical Oncology (example citations below) support ADT intensification.

So, what is the better way to go? Take a vacation or intensification?

To be clear, adding additional drugs to ADT, does not reduce the side effects burden. Instead, it often increases the intensity of the ADT side effects and can add in new side effects. So, as noted above, the patient’s overall health and quality of life need to be taken into consideration when on ADT. With a broad range of options—from intermittent to intensified ADT—it become increasingly important that patients on ADT monitor not just their PSA, but other measures of their health, such as their energy levels and diabetic risk. 

What has been surprisingly missing in the studies that have shown a benefit to intermittent therapy, is the impact of intermittent therapy on not just the patient, but also their partners. We have known for decades that the side effects of ADT on patients can indirectly lower the quality of life of the partners of patients. What we have not seen is studies of the how the partners of PCa patients, who cycling on and off ADT, are doing with each cycle. Do they also benefit? We just don’t know.

With PCa patients living longer with ADT—and with the broadened range of ADT treatment options—it is time to not just study the impact of the various treatment protocols on the patients, but also on their intimate partners.

References:

Becker, B., Stroever, S., Reddy, A., & de Riese, W. T. W. (2023). Comparison of Intermittent and Continuous Androgen Deprivation Therapy in Prostate Cancer Patients: An Up-to-Date Meta-analysis for Urologists and Medical Providers. Urology practice, 10(5), 424–434. https://doi.org/10.1097/UPJ.0000000000000424

Sayyid R & Z. Klaassen (2023) Prostate Radiotherapy for De Novo, Low Volume Metastatic Hormone Sensitive Prostate Cancer: Is There Benefit? UroToday

https://www.urotoday.com/library-resources/mhspc/145327-prostate-radiotherapy-for-de-novo-low-volume-metastatic-hormone-sensitive-prostate-cancer-is-there-benefit.html

Jeremiah Wala, Paul Nguyen, and Mark Pomerantz (2023) Early Treatment Intensification in Metastatic Hormone-Sensitive Prostate Cancer Journal of Clinical Oncology 2023 41:20, 3584-3590.

Vale, C. L., Fisher, D. J., Godolphin, P. J., Rydzewska, L. H., Boher, J. M., Burdett, S., ... & Tierney, J. F. (2023). Which patients with metastatic hormone-sensitive prostate cancer benefit from docetaxel: a systematic review and meta-analysis of individual participant data from randomised trials. The Lancet Oncology, 24(7), 783-797.

Sometimes in Science the Story is in the Missing Data

There’s a new paper out of Finland that may seem unrelated to ADT, but tells an interesting story relevant to men challenged by ADT side effects. The paper is specifically about a questionnaire called the Expanded Prostate Cancer Index (EPIC) used to collect data on the impact of cancer treatments on prostate cancer patients’ quality of life (QoL). A separate study from our own research team (Mainwaring et al. 2023) showed that the EPIC is the second most common survey instrument used to collect QoL data from prostate cancer patients. Indeed, the EPIC has been cited in over 4000 papers over the last 23 years!

The researchers surveyed 625 prostate cancer patients where 12% of the men were on ADT.

What is unusual about this study is the authors not only looked at the questions that the patients answered, but also examined the ones that the patients elected to leave unanswered. The researchers noticed that patients on ADT were more likely than chance to skip answering questions in two areas; those that related to sexual function as well as questions categorized as hormone related. Questions in those two areas ask specifically about things like hot flash bother, frequency of erections, and ability to reach orgasm.

Questions in these areas are particularly problematic for patients on ADT. Many men on ADT are greatly bothered by loss of sexual function and hormonal effects, such as hot flashes. However, others are not, and it can depend on factors such as their age and how adapted they are to the changes in their lives brought on by ADT.

What the authors found is that men, who are not in a sexual relationship, were more likely to leave questions on sexual function unanswered compared to other questions. Note that the question asks “Overall, how big a problem has your sexual function or lack of sexual function been for you during the last four weeks?” Trying to answer that question can be difficult for any man whose sex drive is depressed by ADT, but is also unpartnered. As the authors noted, it is not clear how men on ADT should answer that question or how researchers should interpret their answers. It’s not surprising that so many men on ADT elected to simply pass on the question. 

Another issue with the EPIC is that it only explores the concerns of the patients, yet we already know that prostate cancer treatments affect not only patients, but indirectly their intimate partners. Regrettably, very few studies have looked at any correlation between the answers that the patients gave on QoL questionnaires, like the EPIC, and what answers their partners might give.

There’s been a great push lately for survey instruments that can collect data from patients on questionnaires that can be filled out on a tablet by patients in the waiting room. Such questionnaires are collectively called “patient reported outcome measures”, or PROMs. The EPIC is a PROM which seems to get used a lot simply because it is easy to fill in and has been used by so many past studies. But it may not help us understand what is really bothering patients the most, what is affecting their partners, or what to do about that.

It is often hard for us patients to describe how ADT is affecting our lives. It’s to the credit of the Finnish authors that they recognized weaknesses in the EPIC questionnaire based the questions there that many of the men on ADT decline to answer.

Reference:

Talvitie, A. M., Helminen, M., Ojala, H., Tammela, T., Auvinen, A., & Pietilä, I. (2023). Missingness in the expanded prostate cancer index short form (EPIC-26) — prevalence, patterns, and explanatory factors. Health and quality of life outcomes, 21(1), 89. https://doi.org/10.1186/s12955-023-02175-1

Mainwaring, J. M., Lee, T. K., Wassersug, R. J., & Wibowo, E. (2023). Scales for assessing male sexual function are not entirely applicable to gay and bisexual men with prostate cancer. Urologic Clinics [in press]

A New Meta-Analysis Concludes that ADT is Associated with a Significant Increase in the Risk of Dementia, Parkinson’s Disease, and Depression…but the Interesting Stuff is in the Details

Here we have a new meta-analysis of research on the neurocognitive risk associated with ADT. The study has not been published yet in the peer reviewed literature, but it is available online, and an abstract was published in the spring in the Journal of Urology.

The data was extracted from large retrospective data sets that identify correlations between ADT and select psychological problems for prostate cancer patients. The sample size is impressive; twenty-seven studies are pooled, which collective compare data from over 900,000 prostate cancer patients, who received ADT, with over 1.2 million patients, who did not receive ADT, as well as another 330,000+ patients with neither prostate cancer nor treatment with ADT.

If one only reads the Abstract, the conclusions seem scary. But there are some interesting points buried in the body of the paper not mentioned there.

Granted, the paper documents an increased risk of dementia and depression in prostate cancer patients on ADT, but that has been reported many times before. However, this study goes further and distinguishes Alzheimer’s disease from vascular dementia and also reports an increased risk of Parkinson's disease. Although that was only documented in three of the 27 studies included in the meta-analysis.

Before we dig into the details, one should understand that researchers can most easily find significance differences between populations when the sample sizes are very large, as they are here. Retrospective studies like this can only find correlations, which is not the same as identifying causal links. All the data in this study are presented as hazard ratios, where a significant hazard ratio of 1.66 indicates a likelihood of a 66% increase of the incidence of the condition at the population level. That, by the way, is the highest hazard ratio reported in this study and it’s for depression, which is the best studies neurocognitive disorder assessed with ADT. From other studies, we already know that depression is common with ADT, but not invariable and not demonstrable in the majority of men on ADT.

So, let's get into some of the new findings…

1.There is some hint that the specific form of androgen suppression (i.e., the “treatment modality”) may correlate with the risk of Alzheimer disease, but this warrants further research 

2. Age appears to be a factor with no increased risk for men on ADT younger than 65 but greater risk for men over 65.

3. In comparable studies from around the world, “only cohorts from America showed an increased risk of dementia with ADT.” Since this increased risk was not seen in studies from Europe or Asian, the authors pointed out that “genetic and environmental factors may play a role in modifying the risk of cognitive decline in patients with prostate cancer”.

On this last point, dementia is progressive and not something that can be cured. However, lifestyle interventions—e.g., maintaining a heart healthy diet, controlling one’s weight, and getting a good amount of physical exercise—can all limit the risk of depression and cognitive impairment as we age regardless of whether we are starting on ADT or not.

Reference:

Hinojosa-Gonzalez, D., Zafar, A., Saffati, G., Kronstedt, S., Zlatev, D., & Khera, M. (2023). Androgen Deprivation Therapy for Prostate Cancer and Neurocognitive Disorders: A Systematic Review and Meta-Analysis. https://doi.org/10.21203/rs.3.rs-3221041/v1

Note: A preprint that has been posted on Research Square, but not yet published in a peer-reviewed journal.

When it Comes to ADT, some Patient Reported Outcomes (PROs) Miss the Mark

It is increasingly popular for researchers to use patient reported outcome measures (PROMs) to capture data on the Quality of Life (QoL) of cancer patients. For many of us, who are patients, when one hears of “patient reported outcomes”, we envision a doctor or nurse asking us about how we're feeling, what side effects we're experiencing, and what is the greatest concern to us. In the clinical setting, however, PROMs tend to be captured using questionnaires that patients fill in rather than information gathered through direct conversation with healthcare providers.

In the world of prostate cancer, one of the most popular and commonly used PROMs is the Expanded Prostate Cancer Index Composite; i.e., the EPIC. The EPIC has been around for over 20 years and has been used in over 700 studies. As more researchers use the EPIC, more may assume it’s use is appropriate. However, from our perspective the EPIC has serious limitations when used to assess the QoL of men on ADT.

The EPIC has several separate domains. One is labelled “sexual function.” The questions there don’t actually ask about sexual function, but rather about “how big a problem,” the patient perceives to be having related to their sexual desire, ability to have erections, and ability to reach orgasm over the past 4 weeks.

ADT limits men’s ability to have erections and to reach orgasms, but it also affects sexual desire.

Patients, who are sexually active at the time they start ADT, may either find ways to continue to be sexually active … or they may abandon having sexual activity altogether. Reasons for this differ but may include expectations about the kind of the sexual activity they have, or their partner’s interest in sex. The loss of erections and orgasm may be greatly bothersome, not only to the patient but also the partner if they both have high desire for sex. Alternatively, the same changes may be of little bother for either of them, yet they may have a good, strong, co-supportive, dyadic bond built upon other factors than sex. Aging may also contribute to changes in sexual activity and interest. 

The EPIC questionnaire fails to sort this out. This is because the sexual domain in the questionnaire asks about bother, not function. Both patients and partners may have no sexual function, but also little or no bother from that because they have little sexual desire. Or they may be greatly bothered. There’s no way of telling based on the wording in the EPIC.

What concerns us here is a new study by Movsas et al. (2023), which used the EPIC questionnaire to look at QoL for prostate cancer patients with intermediate risk disease, who either used androgen deprivation therapy short term to support radiotherapy (RT) or got RT without ADT. The participants were surveyed with the EPIC at baseline, at the end of their RT treatments, six months later, a year later, and then five years later.

The EPIC revealed that the patients were greatly bothered by the impact of ADT on their sexual desire, erections, and ability to have orgasms at the end of their RT sessions. However, as time went by, the overall EPIC score for the sexual domain improved in the ADT group. The scores became less extreme and less clinically meaningful.

Had the patients returned to baseline and recovered from the ADT’s impact in the sexual domain? Or had they adapted to (or resigned to) a sex-free life without erections and orgasms secondary to reduced sexual desire? The paper doesn’t say. Furthermore, the researchers did not survey the partners to find out how they were doing. Nothing is said about sexual interests or bother for the partners of the men who had been on ADT.

The paper also reports on another EPIC QoL domain that collected data on whether the patients have experienced in the last four weeks hot flashes, loss of body hair, depression, a lack of energy, and any change in body weight. The results showed major changes in most of these variables at the six-month mark, but less so at the year mark.

Often hot flashes simply diminish overtime, loss of body hair typically occurs within six months and doesn’t change after that. Changes in body weight may be substantial in the first six months, but patients may be taking action to stabilize that so they’re no longer experiencing changes in their weight after months to a few years go by. Once again, one cannot tell whether these QoL features have returned to baseline or stabilized overtime.

This study involved approximately 400 patients. It is not clear though what to make of the authors statement that “PRO differences were relatively short-lived, with no clinically meaningful differences between patients getting ADT or not with RT, by one year after initiating treatment.” That could easily be interpreted to mean that ADT effects are transient and disappear after one year. The paper concludes by saying that instruments like the EPIC “provide added value to help individuals make fully informed decisions among the treatment options.”

When patients are offered ADT, they might like to know what changes might occur that can be easily reversed, and which ones are more permanent. As sexual function impacts both the partner and the patient, to help them make “fully informed decisions among treatment options,” they should both be informed about the changes they’re going to experience that may be difficult to reverse upon completion of short-term ADT. This can include the health and stability of their intimate partnership.

Reference:

Movsas, B., Rodgers, J., Elshaikh, M., Martinez, A., Morton, G. , Krauss, D., Yan, D., Citrin, D., Hershatter, B., Michalski, J., Ellis, R., Kavadi, V., Gore, E., Gustafson, G., Schulz, C., Velker, V., Olson, A., Cury, F., Papagikos, M., Karrison, T., Sandler, H., and Bruner, D. (2023). Dose-Escalated Radiation Alone or in Combination With Short-Term Total Androgen Suppression for Intermediate-Risk Prostate Cancer: Patient-Reported Outcomes From NRG/Radiation Therapy Oncology Group 0815 Randomized Trial. Journal of clinical oncology: official journal of the American Society of Clinical Oncology, 41(17), 3217–3224. https://doi.org/10.1200/JCO.22.02389

Not All Diseases that Become More Common with Aging are at Increased risk from ADT: Consider Glaucoma

There is no getting around the fact that ADT has a wealth of side effects, many of which are common in men as they get older … regardless of whether they are treated for prostate cancer or are on ADT. The risk of certain cardiovascular diseases and diabetes increases with age as does the risk of gaining weight as fat and losing muscle mass. ADT increases those risks.

Given the number and severity of ADT adverse effects it is not surprising that patients worry about whether any sign or symptom of a disease that they experience may in fact be due to being on ADT. We track Internet discussions among advanced prostate cancer patients and almost daily someone asks whether this or that symptom they are experiencing might be due to the fact that they're on ADT.

Against that background, we try to track every possible ADT side effect and examine the quality of the data to support it. We're not just interested in documenting all the adverse effects; we’re also interested in cases where ADT can be excluded from being a causal factor. There is now just that sort of report for open angle glaucoma (OAG).

Glaucoma is common disease due to increased pressure in the eye that can lead to blindness. Glaucoma comes in various forms, but the most common form is open angle glaucoma, and it is more common in people as they age. There is now a report out of Taiwan, which compared the incidents of OAG for 1791 prostate cancer patients on ADT match with 1791 patients not on ADT. The study also had a separate control group of 3582 men not diagnosed with prostate cancer nor on ADT.

The incidence of OAG was the same in the control group and the prostate cancer patients not receiving ADT. That means that prostate cancer itself neither elevates nor decreases the risk of OAG. However, the men receiving ADT showed a significantly lower risk of OAG compared to the two other groups.

This is good news, and it follows a somewhat similar study from Korea, which also showed a significantly lower incidence of OAG in Korean prostate cancer patients treated with ADT compared to patients not on the ADT.

It remains to be seen whether this positive association holds up for men of a non-Asian background.

References:

Yang, P. J., Lin, C. W., Lee, C. Y., Huang, J. Y., Hsieh, M. J., & Yang, S. F. (2023). The Use of Androgen Deprivation Therapy for Prostate Cancer Lead to Similar Rate of Following Open Angle Glaucoma: A Population-Based Cohort Study. Cancers, 15(11), 2915.

Who Regrets Most Going on ADT, and Why?

Over the years we have talked to hundreds of prostate cancer patients, who have previously been on ADT, about how bothered they were by ADT side effects. The responses covered the spectrum. Some patients felt they had no side effects at all. Others swore they would never go back on ADT because they found the side effects so intolerable.

We didn’t ask though whether those who were on ADT short term to improve the effectiveness of radiotherapy used to treat localized disease, had such significant regret that they would decline going back on it, if they experienced “biochemical failure” (i.e., a rising PSA indicative of disease progression).

Concern about ADT regret negatively influencing patients’ willingness to go back on ADT led a group of researchers in Australia to search for factors that influence ADT regret (Booth et al. 2023). The researchers hypothesized that the more bothered a patient was from ADT side effects, the more regret they would have. So, they surveyed 234 patients about the side effects they experienced and how bothersome they were. Next, they asked the patients who had significant regret, what sort of survival benefit they would want to be willing to go on ADT a second time if they experienced disease progression.

The side effects that the patients found most bothersome were the common ones reported from many other studies, e.g., hot flashes, fatigue, and sexual problems. But despite the side effects, the level of regret was over all quite low. Although a third of the men with regret said that they would hope for a >10% survival benefit to be willing to go on ADT again, we don’t know if that would remain true if they were experiencing pain from advancing disease.

In a search for factors that correlate with ADT regret, such as patients’ age, time since treatment, and comorbidities, the one variable that stood out strongly was biochemical failure post-radiotherapy administered with curative intent along with adjuvant ADT. This is hardly surprising. If a patient undergoes any cancer treatment with the hope that it will be curative and it is not, they may view the treatment as a waste of time, with no benefit, just side effects.

What the researchers didn’t consider is how well informed the patients were about ADT side effects beforethey started on ADT. Although Booth et al. (2023) doesn’t cite Wibowo et al. (2020), where we show that educating patients ahead of time about ADT side effects—and ways to manage those side effects—reduce bother from that treatment. Indeed, pre-emptive education increases patients’ self-efficacy in managing ADT side effects.

Whereas education about ADT before starting on the drugs can significantly reduce side effect, neither Booth et al. (2023) nor Wibowo et al. (2000) investigated whether knowing what to expect influences patient willingness to go back on ADT, if they experience biochemical failure after early treatment. Hopefully, Booth et al. or others will follow-up on that.

References:

Booth, V., Eade, T., Hruby, G., Lieng, H., Brown, C., Guo, L., ... & Kneebone, A. (2023). Decision regret and bother with the addition of androgen deprivation therapy to definitive radiation treatment for localised prostate cancer. Practical Radiation Oncology (in press).

Wibowo, E., Wassersug, R. J., Robinson, J. W., Santos-Iglesias, P., Matthew, A., McLeod, D. L., & Walker, L. M. (2020). An Educational Program to Help Patients Manage Androgen Deprivation Therapy Side Effects: Feasibility, Acceptability, and Preliminary Outcomes. American journal of men's health, 14(1), 1557988319898991. https://doi.org/10.1177/1557988319898991

What are the Pros and Cons of Adding a Second Generation Anti-androgen to Standard ADT … and is One Anti-androgen Really Better than the Others in that Regard?

There has been a slew of studies in the last decade showing that intensifying standard ADT with a second generation anti-anti-androgen (AA), such as darolutamide (Nubeqa), enzalutamide (Xtandi) or apalutamide (Erleada), can extend life for prostate cancer patients facing disease progression when curative treatments are no longer an option. As a result, it has become standard protocol to offer one of these three drugs along with ADT to patients experiencing biochemical progression (i.e., a rising PSA) after localized treatment for prostate cancer.

But all drug treatments come with side effects. In that regard, we now have a comprehensive review and a meta-analysis by Nowakowska et al. (2023) of “functional toxic effects” of the AAs when used along with standard ADT. These are the serious side effects that can directly affect how patients feel and function in everyday life.

The meta-analysis involved 12 randomized trials comprised of over 13,500 patients. The median age of the men across the studies was ~70 years and the relevant studies had follow-up from just over a year to four years.

The meta-analysis documented significant increases in fatigue with the addition of AAs to ADT. The authors also “found a 2-fold increased risk of cognitive toxic effects with the AAs.” In addition, they reported that the “AAs conferred an 87% increased relative risk of a fall compared to controls [i.e., men on ADT alone].”

Those are serious side effects. As such, any patient being offered an AA on top of ADT might reasonably want to know, how the three AAs compare in terms of both cancer control and the risk of such “functional toxic effects. 

At the recent 2023 American Society of Clinical Oncology meeting, an abstract was presented by Morgans et al. (2023) that ranked darolutamide as somewhat better than its two competitors in slowing the time prostate cancer takes to progress to metastatic castration-resistant disease. But, what about those serious side effects? That brings us back to the recent metanalysis of functional toxic effects. There, the authors reviewed a 2020 paper by Fizazi et al. showing that the risk of “fatigue, mental impairment disorders, [and] falls” are all increased when ADT is intensified with darolutamide. Nowakowska et al. (2023) define “mental impairment disorders” as including “disturbances in attention.” That links up the three adverse effects. If “cognitive toxic effects” means a patient, who is not paying attention to where he places his feet when walking, and as also suffering fatigue, he is at increased risk of tripping and having a serious fall.

The authors, to their credit, recognize as a key point of their review that there is a need for physicians to “prevent, identify, and intervene on cognitive and functional toxic effects” in patients receiving AAs for prostate cancer. A preventive action that patients can take on their own is to be physically active before they start on the drugs and to maintain a good exercise program while on the drugs.

Sokolova and Graff (2023) provide an accompanying editorial to the Nowakowska et al. (2023) paper, that acknowledge the trade-off between extending life and maintaining a good quality of life. As they succinctly state “men must determine whether the potential benefits of treatment are worth the influence on their quality of life.” That is an all-to-often tough trade-off in the world of cancer. When facing it, prostate cancer patients shouldn’t face it alone but talk it over with those close to them, for their decision will influence not just themselves, but also their loved ones.

References:

Morgans, A., Shore, N., Khan N., Constantinovici, N., Khan, J., Chen, G., Xu, J., Ortiz, J., & George, D. Comparative real-world (RW) evidence on darolutamide (Daro), enzalutamide (Enza), and apalutamide (Apa) for patients (Pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) in the United States: DEAR. Journal of Clinical Oncology, 21(16\_suppl, 5097. https://doi.org/10.1200/JCO.2023.41.16\_suppl.5097

Nowakowska, M., Ortega, R., Wehner, M., & Nead, K. (2023). Association of Second-generation Antiandrogens With Cognitive and Functional Toxic Effects in Randomized Clinical Trials: A Systematic Review and Meta-analysis. JAMA oncology, e230998. https://doi.org/10.1001/jamaoncol.2023.0998

Sokolova, A., & Graff, J. (2023). Balancing Treatment Benefits of Androgen-Receptor Signal Inhibitors and Quality of Life in Patients With Prostate Cancer. JAMA oncology, 10.1001/jamaoncol.2023.0982. https://doi.org/10.1001/jamaoncol.2023.0982

Fizazi, K., Shore, N., Tammela, T., Ulys, A., Vjaters, E., Polyakov, S., Jievaltas, M., Luz, M., Alekseev, B., Kuss, I., Le Berre, M., Petrenciuc, O., Snapir, A., Sarapohja, T., Smith, M., & ARAMIS Investigators. (2020). Nonmetastatic, Castration-Resistant Prostate Cancer and Survival with Darolutamide. The New England journal of medicine, 383(11), 1040–1049. https://doi.org/10.1056/NEJMoa2001342

The Better the Survival, The More we Need to Focus on Quality of Life

A slew of studies in the last half decade or so have compared treating patients, who have metastatic prostate cancer, with ADT alone, or ADT in combination with other agents, notably either abiraterone and prednisone or a second-generation anti-androgens. These combinations have come to be known as “doublet therapy.” If one adds in a chemotherapy agent like, docetaxel, that is now referred to as “triplet therapy.” Collectively these studies have pointed to better survival for these advanced patients when ADT is combined with at least one of the newer agents.

As patients survive longer on these intensified treatment protocols, it becomes important to look at not just their survival, but their health-related quality of life (HR-QoL). Inspired by that concern, an international group of uro-oncologists reviewed six important studies that have shown the benefit for prostate cancer treatment intensifications. Here the researchers focused specifically on patients’ HR-QoL.

As a general conclusion, the authors found that either enzalutamide or abiraterone, when combined with ADT, increased overall HR-QoL compared to ADT alone.

The authors flagged though a major problem in comparing these studies; i.e., they used a wide variety of measures of HR-QoL making it difficult to compare the studies. For example, two studies focussed on the time to “clinically meaningful deterioration.” Another looked at “patient reported deterioration.” Some looked at “progression;” others looked at “physical symptoms.” They may sound similar, but they are not.

The authors found in general that the combinations did not improve sexual function and the authors believed that was simply because the ADT alone would have greatly suppressed sexual function.

Patients were more likely to report loss of appetite, if they were taking enzalutamide and ADT rather than just ADT. The combination of darolutimide, ADT, and docetaxel led to a longer time to pain progression compared to ADT alone.

The studies were inconsistent in terms of what they reported on in terms of “emotional well-being” and “social and family well being.” None of the studies looked at the well-being of the intimate partners and caregivers of the patients.

In their key last paragraph, the authors write “We plea for a standardization of measurements to allow quantitative comparisons across future studies.” We would add to this that future studies should also look at the HR-QoL and welfare of the partners and caregivers of the patient’s since it has been known for a long time that ADT not only burdens prostate cancer patients directly, but indirectly also their loved ones.

Reference:

Afferi, L., Longoni, M., Moschini, M., Gandaglia, G., Morgans, A., Cathomas, R., Mattei, A., Breda, A., Scarpa, R. M., Papalia, R., de Nunzio, C., & Esperto, F. (2023). Health-related quality of life in patients with metastatic hormone-sensitive prostate cancer treated with androgen receptor signaling inhibitors: the role of combination treatment therapy. Prostate cancer and prostatic diseases, 10.1038/s41391-023-00668-0. Advance online publication. https://doi.org/10.1038/s41391-023-00668-0

Let's Talk about Prostate Cancer and Depression

There is a lot you can learn from the massive datasets acquired in the countries that keep national health registries. The National Prostate Cancer Registry of Sweden, for example, has data on almost 200,000 men diagnosed with prostate cancer between 1998 and 2017. With samples that size, one can look at slew of factors that can influence serious, but rare outcomes of a cancer diagnosis and its treatment. A good example is the risk of depression and suicide for men with prostate cancer. And we now have a registry study from Sweden that looked at exactly that.

The authors of this new study found that men diagnosed with high-risk PCa have substantially higher rates of major depression and suicide relative to men without PCa. These risks remain high >10 years post diagnosis. In contrast, men with low or intermediate risk PCa have modestly higher rates of major depression and slightly elevated risk of suicide, but this is only seen in the first year after their diagnosis.

Other factors that came into play in terms of an elevated risk of depression are having lower education, lower income, and also having had a previous history of depression before the prostate cancer diagnosis.

What also stands out for us, and it is relevant to readers of this blog now, is ADT was a contributory factor for depression in the advanced patients.

One of the strengths of this study was that the researchers could compare all the prostate cancer patients to other men in the health registry that were matched with the cancer patients in terms of the age and any comorbidities that they had.

A diagnosis of prostate cancer itself can raise the risk of depression. But when the cancer is of low risk and patients realize that they can have many years of life, the risk of depression declines within a year or so. Patients, however, who are diagnosed with more advanced disease are in a different and more challenging situation; they are more likely to go on ADT and if the disease progresses, the risk of depression goes up. Here both treatment with ADT and disease progression, or the fear of it, exacerbate pre-existing depression.

What we believe the major take home message from this study is not that ADT causes men to become suicidal, for the number was extremely low in this population; i.e, just one in 500 of the advanced patients. However, the incidents of major depression were about 8% of the men in this study. That led the authors to push for men diagnosed with prostate cancer to be screened for depression. Our take on that is that it's important that patients, who have had episodes of major depression and are starting an ADT, to be aware of the risk and to inform their clinicians of their history. We agree with the authors as well, that along with monitoring the status of the patients’ cancer, their mental health should also be assessed, particularly if they go on ADT.

Reference:

Crump, C., Stattin, P., Brooks, J. D., Sundquist, J., Bill-Axelson, A., Edwards, A. C., Sundquist, K., & Sieh, W. (2023). Long-term Risks of Depression and Suicide Among Men with Prostate Cancer: A National Cohort Study. European urology, S0302-2838(23)02787-2. Advance online publication. https://doi.org/10.1016/j.eururo.2023.04.026

Should the Presence of Visceral Metastases Make a Difference in Treating Patients with Advanced Prostate Cancer?

Typically, when prostate cancer spreads beyond the prostate gland, the metastases show up in the skeleton system. However, with improved imaging, such as with PSMA diagnostic scans, oncologists are increasingly finding prostate cancer in the viscera as well.

In patients with metastatic disease, the standard treatment is not just ADT, but ADT combined with either abiraterone and prednisone or one of the newer anti-androgens, such as enzalutamide.  

A group of researchers asked a simple question: Does the presence of visceral mets make a difference in terms of what is the best treatment for the patient? To find the answer, the authors reviewed data from six, relatively recent, phase III trials that included almost 5400 patients. Out of that sample, just over 15% of the patients had visceral metastasis. Based on the study the authors reviewed, some patients were treated with a newer anti-androgen while others received abiraterone acetate and prednisone.

The winner here was the abiraterone and prednisone. For patients with visceral mets, abiraterone and prednisone combined with ADT improved overall survival better than anti-androgens and ADT.

This confirms how important it is to have good imaging when dealing with a rising PSA after treatment for localized disease. Knowing where the disease is in the body helps physicians to come up with the best personalized treatment.

Reference:

Yekedüz, E., McKay, R. R., Gillessen, S., Choueiri, T. K., & Ürün, Y. (2023). Visceral Metastasis Predicts Response to New Hormonal Agents in Metastatic Castration-Sensitive Prostate Cancer. The oncologist, oyad102. Advance online publication. https://doi.org/10.1093/oncolo/oyad102