Experts Urge Early Therapy and Less Delay in Treating Advanced Prostate Cancer

Raoul S. Concepcion, MD

Amid an expansion of therapeutic options for men with advanced prostate cancer, evidence is building that introducing recently developed agents and regimens earlier in the treatment timeline can benefit patients in several disease settings.

That was the central take-home message from an OncLive Peer Exchange® panel of experts who participated in a roundtable entitled “Treatment of Advanced Prostate Cancer: Expert Evaluations on Recent Articles and Studies.” The panel included specialists in urology and medical oncology.

“Recent and emerging data are providing signals as to the benefits of early treatment in patients who have high-grade prostate cancer,” noted Raoul S. Concepcion, MD, who served as moderator for the discussion. The panelists explored the results of several studies that addressed questions related to the treatment of patients with or without frank metastatic disease. In addition, the panel looked at mechanisms of resistance to therapy and the potential impact of early treatment.

Repeatedly, the discussion returned to the fact that there is an array of useful drugs available for these patients and, as Michael Fabrizio, MD, said, “all of these drugs need to be used earlier in the spectrum of the disease. The key is to treat these patients earlier, recognize advanced disease earlier.”

In light of the potential options, “defining your goals of treatment” for each patient is an essential step, noted Jorge A. Garcia, MD. Doing so will help clinicians determine “which is the best agent for that particular patient,” he said.

Initiating Enzalutamide and Abiraterone

The panelists cautioned that it is probably important not to be overly focused on which patient has metastatic disease and which patient has disease that has not metastasized. All of these patients “have systemic disease and that’s really the crux of the issue,” Charles J. Ryan, MD, said. Garcia reinforced that comment, adding, “I think all of us recognize the fact that M0 patients do have metastatic disease,” although current technology “is not allowing us to detect that metastatic disease.”A recent study in The New England Journal of Medicine reported that patients with castration-resistant prostate cancer (CRPC) with androgen report (AR) splice variant 7 messenger RNA (AR-V7) detected in their circulating tumor cells had no clinical benefit whatsoever from either enzalutamide or abiraterone acetate, two therapies directed at the AR.¹

Michael Fabrizio, MD

The study is important, Garcia said, in relation to biomarker development for prostate cancer. The study points to “one of the first examples of truly personalized medicine that could come to the forefront” in CRPC, explained Judd W. Moul, MD.

However, the relevant technology is not commercially available at the present time. So the findings of this study cannot be brought into the clinic at this time.

As to when to start enzalutamide or abiraterone, current indications are that, “the earlier intervention, the better,” for patients with chemotherapy-naïve CRPC, said Ryan. “If you’re waiting for a patient to suffer and have pain or complications, you’re waiting too long.” With some patients, those for whom PSA levels do not decline upon receiving AR-targeting therapy, the drugs might soon be stopped. “I really believe these agents that target AR must, with a big capital MUST, lower your PSA,” Garcia said. “I typically go 12 weeks. If I haven’t seen a PSA decline at all, they’re off the therapy and on to something else,” added Ryan. “And, actually, we now know that these might be the patients with the V7.”

Integrating Radium-223 Therapy

Data on patients taking abiraterone for more than 17 months show the agent is well tolerated, although blood sugar levels may be affected. Importantly, the risk from the corticosteroids given along with the drug is low.Radium-223 is the first radiopharmaceutical that has a documented survival benefit. In the pivotal ALSYMPCA trial, patients who received radium- 223 plus best supportive care achieved a median 14.9-month overall survival compared with 11.3 months with placebo and best supportive care.² The participants in that trial were required to have minimally symptomatic or asymptomatic disease without visceral metastases. “But more important than that is how much pain you needed to have to be enrolled,” said Garcia. “Actually around 40% of patients or so were not taking opioids, suggesting that you don’t need to be taking opioids to achieve benefit from this therapy.”

Jorge A. Garcia, MD

Garcia said radium-223 does not provide an approach to quick pain relief. If the patient has “a lot of pain needs and you need rapid pain control, I personally don’t believe radium-223 is the right agent,” he said. “You can actually get rapid pain control with systemic chemotherapy within a week of therapy. If you look at the median time to pain control [with radium-223], on the phase I/II data, it’s around three cycles.”

Thus, identifying good candidates for radium- 223 requires some probing, since many men are reluctant to admit they are experiencing a level of pain. For example, Fabrizio pointed out, the patient who is on a baby aspirin or Tylenol for pain and has failed to tell the nurse about this medication may require gentle questioning during discussions with the patient or the family before he will admit to some level of pain.

In addition, radium-223 is appropriate, for example, for the patient with multiple bony metastases where one specific spot clearly is the symptomatic lesion, a context in which radium-223 may be combined with local external beam radiation therapy directed into that area for pain.

Charles J. Ryan, MD

When a patient is given radium-223, panel members continued administration of oral therapy, although combining radium-223 with chemotherapy may entail challenges. Further, the panel members use radium-223 not to replace denosumab but along with denosumab, as was evident in data from the radium-223 expanded access program reported earlier this year.³

Timing Sipuleucel-T

An important point is that, as Concepcion said, radium-223 is an alpha particle and carries a far lower risk of myelosuppression than did the beta radiopharmaceuticals that were used at one time, although there is still a risk. As Garcia said, “the biggest question is how do you support those patients” His group sees these patients on a monthly basis, whether the contact is with a nurse practitioner, a physician assistant, or a physician.Sipuleucel-T is an immunotherapy agent custom made from antigen-presenting cells that are harvested from the patient through plasmapheresis, then cultured to activate immunogenicity, and infused into the patient. The treatment course consists of three intravenous infusions. The IMPACT trial demonstrated a 4.1-month median OS advantage for patients taking the drug compared with a placebo.⁴ In a secondary analysis that correlated response and survival data with participants’ baseline PSA levels, the survival benefit for patients with PSA of <22 was greater than 1 year.⁵

Mauro said that finding was “striking,” but noted that sipuleucel-T remains a subject of much controversy in the field.

Judd W. Moul, MD

Concepcion noted that patient selection is key with sipuleucel-T. He said American Urological Association guidelines support the therapy for patients who are asymptomatic with the prospect for significant survival. The treatment has a relatively mild adverse-event profile and helps preserve quality of life, a factor so important to these patients. “If you’ve got an ECOG 0 patient who’s going to live at least 12 months, who’s completely asymptomatic, you should be considering sipuleucel-T,” said Concepcion, although he noted that controversy over layering and sequencing of therapies remains unresolved.

When to Use Chemotherapy

“If you give sipuleucel-T in that sweet spot, it’s very cost effective,” noted Ryan. However, he said giving the drug to patients who are “not in that sweet spot“ would be “wasting money.” For example, if a patient has already received docetaxel and has progressed, Ryan said, “this isn’t the time to bring in the sipuleucel. You missed that window and you move on.”The panel emphasized both the importance of chemotherapy for patients with metastatic prostate cancer and the importance of starting chemotherapy early. “Chemotherapy is, in fact, the new standard of care for men with castration-sensitive disease, with metastatic disease,” said Garcia.

Data reported during the past 3 years indicate that “it is possible that if, indeed, chemotherapy actually can be given earlier to a very selective group of patients, your outcome is likely to do better than if you wait until someone has a lot of symptoms,” Garcia said. “In the context of castration-resistant disease, I don’t think you really need to wait for having someone with a lot of symptoms to start chemotherapy.”

Notably, the CHAARTED study demonstrated that median overall survival was 13.6 months longer with docetaxel plus androgen-deprivation therapy (ADT) than with ADT alone (57.6 months vs 44.0 months, respectively; HR, 0.61).⁶ The study, also known as ECOG 3805, enrolled 790 patients with metastatic, hormone-sensitive prostate cancer; approximately 65% of the participants had high-volume disease and about 73% had not received prior local therapy.

Emerging Role of Biomarkers

“When you look at the CHAARTED data, there is no doubt that adding chemotherapy up front drastically impacts survival,” said Garcia. “The question that now remains is low-volume [disease]. Should low-volume patients go on and get systemic chemotherapy?”Throughout the discussion, the panelists noted the need for biomarkers to help guide clinicians in matching patients with therapies. Although useful biomarkers are not currently available in the clinic, such biomarkers are on the way, and within the next 5 to 10 years are likely to transform the therapeutic approach for these patients, several panelists indicated.

“We don’t have the answers yet,” said Ryan, who pointed out that at present there is not yet a uniform language or a uniform approach to outcome analysis. Further, since CRPC is a polyclonal disease, the preliminary findings now appearing in journals remain insufficient as guides to clinical decisions. Beyond that, the drugs used to treat these patients induce mutations, thus changing the tumor environment.

Nevertheless, the time is rapidly approaching when all specialists treating patients with prostate cancer will need a working knowledge of the underlying biology of the disease. “If you would have told me five or six years ago that as a practicing urologist in independent community practice, that I had to have a working knowledge of the androgen receptor in order to manage my patients with prostate cancer, I would have said you were completely out of your mind, there’s no way,” Concepcion noted. “Whether you’re involved in a multidisciplinary clinic, whether you’re in independent practice, small practice, large practice, I think to better take care of these advancing prostate cancer patients [that knowledge] is going to be critical.”

References

1. Antonarakis ES, Lu C, Wang H, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014;371(11):1028-1038.
2. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.
3. Saad F, Carles J, Gillessen S, et al. Radium-223 in an international early access program (EAP): effects of concomitant medication on overall survival in metastatic castration-resistant prostate cancer (mCRCP) patients. J Clin Oncol. 2015;33(suppl; abstr 5034).
4. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411-422.
5. Schellhammer PF, Chodak G, Whitmore JB, et al. Lower baseline prostate-specific antigen is associated with greater overall survival benefit from sipuleucel-T in the Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) trial. Urology. 2013;81(6):1297-1302.
6. 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.