Recap: Recent Advances in the Treatment of Metastatic Castration-Sensitive Prostate Cancer

At an Around the Practice^® program hosted by CancerNetwork^®, experts spoke about treatment options for patients with prostate cancer, specifically the use of doublet or triplet therapy. The discussion was led by Neeraj Agarwal, MD, Presidential Endowed Chair of Cancer Research as well as director of both the Genitourinary Oncology Program and the Center of Investigational Therapeutics at the Huntsman Cancer Institute of the University of Utah in Salt Lake City, where he serves as professor of medicine.

The other panelists were Simon Chowdhury, MD, PhD, a consultant medical oncologist with Guy’s and St Thomas’ NHS Foundation Trust in London, United Kingdom; Bobby Liaw, MD, assistant professor of medicine, hematology, and medical oncology at Mount Sinai in New York; and Benjamin H. Lowentritt, MD, FACS, director of both minimally invasive surgery and the Robotics and the Prostate Cancer Care Program at Chesapeake Urology in Towson, Maryland.

CASE 1

• Patient characteristics (presentation, April 2019):
  • A 63-year-old man presented with urinary retention and fatigue.
  • His past medical history was unremarkable.
  • Transrectal ultrasound and biopsy showed adenocarcinoma of the prostate gland, a Gleason score of 8 (4 + 4), and disease in 10 of 12 cores.
  • The patient lives an active life.
  • He underwent a radical prostatectomy with negative margins.
  • The pathology report confirmed T3 prostatic adenocarcinoma with no positive lymph nodes.
  • The patient was lost to follow-up and he re-presented in July 2022.
• Workup (July 2022):
  • Prostate-specific antigen (PSA) level was 45.2 ng/mL; hemoglobin was 9.7 g/dL; and absolute neutrophil count was 1.7 x 10³/µL.
  • A bone scan showed 6 bone lesions, including 2 in the left femur.
  • CT scans in the abdomen and pelvis showed no evidence of soft tumor metastasis except for retroperitoneal lymphadenopathy.
  • ECOG performance status was 0; no other comorbidities were present except for hypertension, which was controlled with medication.
• In a discussion about further treatment, the patient expressed a desire for aggressive treatment.
• The patient was treated with androgen-deprivation therapy (ADT) plus apalutamide (Erleada).

AGARWAL: How did decide on the treatment path you did?

Chowdhury: I have been involved in the TITAN study [NCT02489318] as one of the clinical chairs, so I have [vast] experience with apalutamide.¹ We know that a significant subgroup in the TITAN study [benefited from therapy] and we know that that subgroup continued to show a benefit. This is a very reasonable treatment. The best evidence [from TITAN] supports apalutamide, and enzalutamide [Xtandi] is supported by the ARCHES study [NCT02677896], and both are very reasonable treatments.² Certainly in my own practice, we have a lot of experience with apalutamide from TITAN for routine clinical practice. We also use the drug in nonmetastatic [castration-sensitive prostate cancer (CSPC) based on results from the phase 3 SPARTAN trial (NCT01946204)]. Doublets rather than ADT alone have been shown to produce a significant benefit, and sometimes we underestimate that. [This patient] has a poor prognosis and high-volume disease; he isn’t someone with a super scan and a PSA level of several hundred ng/mL. Sometimes we can underestimate the disease and the lethality of disease in a man who has many years to live and is young.

Agarwal: How do you determine a treatment based on the available options for a certain patient?

Liaw: [The results of] multiple studies have shown us that moving some of the drugs that we once reserved for castration-resistant disease into the hormone-sensitive metastatic setting gives us a much more augmented long-term disease benefit in terms of disease control and overall survival [OS] benefit. I will talk to a patient who has high-volume disease about 4 options: docetaxel; apalutamide, such as what was done for this particular patient; abiraterone [Zytiga]; and enzalutamide. In someone who might have low-volume disease, sometimes there’s a good discussion as to whether we do prostate radiation. In this case, he doesn’t have a prostate anymore, so we wouldn’t talk about that. But for de novo metastatic low-volume disease, you might think about that.

Often patients question how we choose among these 4 agents to use for systemic therapy, and no one necessarily has the right answer. Many times, it does come down to the patient themselves and their characteristics. In a patient like this who otherwise has an excellent performance status, is young, and has very few comorbidities, he’s [a candidate] for all treatment options, vs some patients who might have more issues with steroid use, which would make things like abiraterone a bit harder for us to challenge them with. Patients who have hepatic or renal insufficiency might not be quite as good candidates for chemotherapy. One last thing that sometimes comes into the mix is cost issues with medications. For drugs like abiraterone which are off patent at this point, the price point might be more attractive, vs a drug like enzalutamide or apalutamide that is still branded.

Agarwal: How do you decide among the 4 options to treat prostate cancer?

Lowentritt: In 2019, apalutamide and enzalutamide got their approvals in the metastatic CSPC [mCSPC] space.^3,4 Until then, only chemotherapy and abiraterone were available, and only 30% of people received abiraterone, so you still had the vast majority of people getting ADT alone. When I see my patients today and I talk to my partners and colleagues, it’s important to get to that first level of understanding that we need to intensify their therapy. Plenty of evidence shows that the standard of care [SOC] has long evolved past ADT alone. When I’m talking to my patients now with a menu of offerings, I still do counsel them and encourage them. It is very clear that an oral option is often favored, although [in the future,] ways will evolve where they’re not necessarily mutually exclusive.

Abiraterone is still a wonderful medication because the exposure is a little bit longer in this part of the disease state, and patients will be on this for a longer period. There’s a slight concern about chronic steroid use in these patients. I don’t know if that weighs heavier than the other concerns about chronic exposure to these medications on other systems in the body, but that’s a component of it. There’s also a considerable cost-saving for patients who will be on drugs for a long time, so I definitely consider abiraterone as an excellent option. I have used both other options that are approved, apalutamide and enzalutamide, in this space, and there are differences. I tend to avoid enzalutamide in my elderly patients. My personal experience is there can be some increased level of problems with equilibrium or memory or just word finding for those patients over the long haul. I do think we have to recognize that this will be a longer course of therapy. Thankfully they’re all successful in extending life and having a long course, so I have these discussions [with my patients]. I try to do personal assessments, and there are some drug-drug interactions, although they’re minimal. Thyroid disease is more of a unique marker for apalutamide, but it generally occurs as small incidents and is easily managed. I have these discussions, but it ends up being a personal choice based on a lot of individual patient factors.

Agarwal: How do drug interactions play a role in your clinic? When do you decide to switch an anticoagulant rather than the prostate cancer treatment?

Liaw: In my personal practice, we do run into drug interactions here and there. It usually boils down to what options we have for anticoagulants and for treatment of prostate cancer. If their need for coagulation is a much more urgent issue, like in someone who has a saddle embolism, I’m not touching their anticoagulant. It’s more of an issue and is my bigger priority. For prostate cancer, if there are other equally suitable options and I can easily make a substitution, I’m willing to do so if it’s a drug interaction issue. I don’t come up against these tough decisions daily, but here and there we do have to make a decision to switch away from one drug to another.

Agarwal: When looking at the quality of life, why choose ADT plus apalutamide?

Chowdhury: For quality of life, we look at the studies, personal experiences, and at the patient in front of us—and sometimes we underestimate how scary it is for a patient faced with metastatic disease. Patients like this want the best treatment. Sometimes because ADT works well, it’s an active treatment. It’s among the most active treatments we have in solid tumor oncology. We focus on the current outlook rather than thinking about what’s coming for the patient in a relatively short period of time. We see that [progression-free survival] on ADT alone is 12 to 18 months, and it’s shorter in terms of PSA, which obviously drives decision-making anxiety and treatment change. What I discuss with them are the data.

I honestly believe ADT is an elephant in the room. In the [United Kingdom], we underestimate toxicity to the detriment of our patients. Going forward, particularly in patients with lower-volume disease and good responses. I’m hoping we’ll see the escalation of therapy, particularly ADT, and get men on single-agent AR [androgen receptor] inhibitors, although that is not [an approved indication].

Something that we’ve talked about quite a lot in studies such as TITAN, ARCHES, and ARASEN [NCT02799602] is that PSA was blinded to patients and investigators.⁵ The benefit of PSA psychologically is massive for patients. When patients walk into our clinic room, one of the first, if not the first, question is about PSA. PSA is critical and PSA responses—the depth, duration, and how that also ties in with the quality of life—are important. For me, apalutamide and darolutamide [Nubeqa] are both good drugs. I chose apalutamide because of my experience in TITAN.

CASE 2

• Patient characteristics (presentation, May 2021):
  • A 59-year-old man presented to the emergency department with severe pain in his right thigh.
  • His past medical history was unremarkable.
  • Imaging showed an unprovoked fracture in his right thigh.
• Workup:
  • PSA was 500 ng/mL; hemoglobin was 9.8 g/dL; and absolute neutrophil count was 1.7 × 10³/µL.
  • Transrectal ultrasound and biopsy showed adenocarcinoma of the prostate gland and a Gleason score of 8 (4 + 4).
  • Bone scans showed 8 bone metastases, including in the femur and vertebrae.
  • CT scan of the abdomen and pelvis showed peritoneal lymphadenopathy.
  • His ECOG performance score was 0 with no other comorbidities.
• The patient was diagnosed with de novo high-volume mCSPC.
• The patient was treated with ADT plus docetaxel and abiraterone.

Agarwal: Why did you choose to use triplet therapy for this patient?

Liaw: In a case like this, we have many of the same options that we spoke about earlier in terms of doublet therapy. One thing to highlight is that this is a patient who has come in with de novo disease, which typically has a worse prognosis vs [a case where] metastatic recurrence has come back on the metachronous end. We want to put our best foot forward, so to speak. He is a 59-year-old patient who is otherwise independent with no medical issues, and he is also highly symptomatic. He has already had a pathologic fracture. His PSA numbers are tremendously elevated. Everything leads to not just high-volume disease, but many aspects of this disease that are high risk as well.

Data that support the use of triplet regimens like ADT, docetaxel, and abiraterone—a regimen that was championed in the PEACE-1 study [NCT01957436]—and the backdrop of understanding the [benefit of] adding an additional layer of intensification to doublet combination therapy have led to success across all the different agents for mCSPC.⁶ [The PEACE-1] study looked to push that envelope a little bit further by adding on a third agent. We know that prostate cancer has some intrinsic heterogeneity. There will be some early clones that are more inherently insensitive or resistant to ADT, or maybe AR-directed therapy, through mechanisms such as AR variants or alterations. Trying to have something in the chemotherapy category as well as the AR-directed category, investigators hoped to show that a triplet regimen would elevate survival on top of just ADT plus docetaxel alone.

PEACE-1 has an interesting study design; it evolved as the SOC evolved. It was initially designed as a large randomized study to test whether the addition of abiraterone or radiation therapy, or the combination of both, to the SOC of ADT would benefit men with hormone-sensitive prostate cancer. However, [the SOC changed] as data from the CHAARTED trial [NCT00309985] and the STAMPEDE trial [NCT00268476] came out showing the additional benefits of docetaxel.^7,8 [PEACE-1] laid out a prespecified statistical plan that provides for primary efficacy analysis of survival with the addition of abiraterone to the docetaxel-treated population. This study was very positive, but more to our point, the triplet regimen focused on the population of patients who got both ADT and docetaxel as part of the SOC. The addition of abiraterone demonstrated significant improvement in OS with a hazard ratio of 0.75 [95% CI, 0.59-0.95; P = .017]. This positive effect on OS was primarily pronounced in the patients with high-volume disease. The addition of abiraterone to hormonal therapy [must be] seriously considered because it is linked to a survival benefit.

Agarwal: As a urologist, how do you choose between doublet and triplet therapy?

Lowentritt: The latest data indicate that only about 3% of [patients] were getting docetaxel for metastatic hormone-sensitive disease. It’s hard to call that the SOC, so you would love to see what the results are. My focus now is on intensifying therapy up front for these patients with high-volume disease who can tolerate it. Even in the ARCHES and TITAN trials, you had patients who had received docetaxel and then were put on oral therapy. [Patients enrolled were] usually in the low double digits or high single digits in those trials, but they did well and there were prespecified analyses to look at those that did equally well. [Some] data suggest that patients don’t do worse when we combine [treatments].

Now, it’s about finding those patients whom my medical oncology colleagues will treat and the ones who will tolerate [treatment] well. Patients are [presenting at a] younger age, with better performance status, and they undergo a more intensified treatment up front due to high-volume disease. We are seeing this increased incidence of high-volume de novo disease, likely linked to decreased screening in the United States in the last 5 to 10 years. Regardless, we were seeing that trend even before then, and this disease seems to be getting worse. I do think it’ll be about finding those patients who fit the criteria and can go through [docetaxel plus oral therapy] together. We do not give cytotoxic chemotherapy in our practice; we give all the other types of therapies. It’s about the patients having a good discussion with us and then making sure they have access to the medical oncologist, who can have a discussion with them and give them more details. That’s how I have approached it.

Agarwal: How is the process different if the patient has low-volume disease but is still de novo?

Liaw: PEACE-1 also included patients with low-volume disease, and it also tried to determine what type of [patient] benefited from the triplet regimen. As of the most recent data analysis, [we have no conclusive answers] in terms of OS benefit for these low-volume patients. Further longitudinal follow-up may change that, but right now, not a lot of strong evidence shows that patients with low-volume disease would necessarily benefit from a triplet regimen. I’m generally not going to convince patients with low-volume disease to take 3 different therapies at the same time. Some exceptions to that [exist,] because when we define high-volume disease, we’re looking at the CHAARTED criteria, which are primarily focused on a [particular] number of lesions. It doesn’t get at the heart of the matter, which is the overall volume of disease. One tiny, half-millimeter bone lesion still counts as a bone lesion in the CHAARTED trial. If you have a 10-centimeter lymph node that’s obstructing kidney function, that’s still 1 lesion. CHAARTED doesn’t fully accommodate some well-known poor prognostic features of disease, such as a Gleason score or height of PSA [bounce].

There are some gray areas here, [such as if a patient] has low-volume disease and large, obstructive lymph nodes that don’t quite meet high-volume disease criteria. If they’re highly symptomatic and they need an immediate response, I think there’s still room to make a case for much more aggressive triplet therapy. Does that mean that it’s necessarily better over a doublet? I don’t have those data. I don’t know that we’ll have great randomized prospective studies to be able to demonstrate this soon. Most likely, what we’ll have to do is come together as a medical community to understand what the real-world data tell us, to help inform some of these decision-making processes. For patients with low-volume disease, I’m still mostly thinking about doublet therapies.

Agarwal: How do you approach genomic profiling?

Chowdhury: [We have] both germline genomic profiling and somatic genomic profiling. From the somatic genomic profiling [perspective], it’s difficult because many patients [with homologous recombination repair gene alteration] from the PROfound study [NCT02987543] failed the FoundationOne testing.⁹ A lot of the samples had insufficient DNA extraction, so we need to think about that. When we have a patient with metastatic disease, particularly poor-prognosis metastatic disease, we need to be getting the DNA from those patients to check whether they have somatic mutations or germline mutations. Those are patients who will need options going forward, potentially like a PARP inhibitor.

From the germline side, the [National Comprehensive Cancer Network] guidelines are good. We don’t have [enough] geneticist capacity in the [United Kingdom] for every high-risk localized
patient. One must be a bit more pragmatic and look at particularly high-risk [ancestry] groups, such as Ashkenazi Jews [and others] with a significant history of likely BRCA-related cancers, and [consider] education around that. It’s an evolving field. Tests are evolving, and not all genes are equal. BRCA1, BRCA2, and ATM are different genes with different actionability. Not all mutations are equal, so a homozygous deletion is different than a missense. And not all tests are equal. We must be careful about tests that [identify] mutations that just aren’t actionable. A lot of work [remains] to be done there. It’s an interesting area, and you and your group demonstrated with olaparib [Lynparza] that there is actionability that can benefit patients. These are exciting times, but the data are early.

Lowentritt: [My center] was a trial site for PROfound, but I got 0 patients enrolled because all my samples failed. It informed how I then started doing testing, and I am now getting fresher biopsies at diagnosis. I’m getting an initial somatic workup because the tissue is fresh. [Genetic testing] is more likely to be successful, and we have more [available samples] so that we can [determine results easier]. If a prostatectomy [has been done], that makes [genetic testing] easier as well. Most patients who we’re diagnosing with de novo metastatic disease are going to just have a biopsy. I’m [receiving tissue samples] upfront with the understanding that many of these [mutations] are currently actionable. My approach now is to test early and test often. We have to recognize that most of the information that we currently know is helpful is available at the beginning. Future discovery will be based on resistance mechanisms and other things that are developing over time, so we can test as patients progress. I have gone to a lot more testing in the de novo setting.

References

1. Chi KN, Chowdhury S, Bjartell A, et al; TITAN Investigators. Final analysis results from TITAN: a phase III study of apalutamide (APA) versus placebo (PBO) in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) receiving androgen deprivation therapy (ADT). J Clin Oncol. 2021;30(6 Suppl):abstr 11. doi:10.1200/JCO.2021.39.6_suppl.11
2. Armstrong AJ, Azad AA, Iguchi T, at al. Improved survival with enzalutamide in patients with metastatic hormone-sensitive prostate cancer. J Clin Oncol. 2022;40(Suppl 15):1616-1622. doi:10.1200/JCO.22.00193
3. FDA approves apalutamide for metastatic castration-sensitive prostate cancer. FDA. September 18, 2019. Accessed August 10, 2022. https://bit.ly/2lVOeve
4. FDA approves enzalutamide for metastatic castration-sensitive prostate cancer. FDA. December 17, 2019. Accessed August 10, 2022. https://bit.ly/3JLNAHA
5. Smith MR, Hussain M, Saad F, et al; ARASENS Trial Investigators. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med. 2022;386(12):1132-1142. doi:10.1056/NEJMoa2119115
6. Fizazi K, Foulon S, Carles J, et al; PEACE-1 Investigators. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design. Lancet. 2022;399(10336):1695-1707. doi:10.1016/S0140-6736(22)00367-1
7. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373(8):737-746. doi:10.1056/NEJMoa1503747
8. James ND, de Bono JS, Spears MR, et al; STAMPEDE Investigators. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017;377(4):338-351. doi:10.1056/NEJMoa1702900
9. Thiery-Vuillemin A, de Bono J, Hussain M, et al. Pain and health-related quality of life with olaparib versus physician’s choice of next-generation hormonal drug in patients with metastatic castration-resistant prostate cancer with homologous recombination repair gene alterations (PROfound): an open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23(3):393-405. doi:10.1016/S1470-2045(22)00017-1.