"It gives me a very rewarding experience…. I see patients with low-grade prostate cancer and when they become advanced prostate cancer, I already have a good relationship with them and don’t have to send them somewhere else," says Abhinav Sidana, MD, MPH.
Most patients with advanced prostate cancer who would benefit from treatment intensification are not receiving it—despite strong data supporting its use.
“Combining standard androgen deprivation therapy (ADT) with things such as chemotherapy and/or novel hormonal therapies has resulted in significantly improved outcomes. By that I mean improved survival, decreased disease progression, and increased quality of life. This has led to…FDA approval of these agents in that setting…[and] now [to] treatment intensification…[becoming] part of the guidelines,” said Vitaly Margulis, MD, professor and Paul C. Peters, MD, Chair in Urology at UT Southwestern Medical Center in Dallas.
Moreover, treatment intensification for advanced prostate cancer is not new, with large trials being published in 2015, according to Jason M. Hafron, MD, chief medical officer and director of clinical research at the Michigan Institute of Urology in West Bloomfield.
“Historically, patients have been treated with androgen deprivation therapy alone…[and have done]…OK with…[it], but in the last 8 years we’ve had major…international phase 3 trials that show that ADT monotherapy is no
longer acceptable and that treatment intensification will significantly benefit patients’ overall survival,” said Hafron, who is also a professor of urology at Oakland University William Beaumont School of Medicine in Royal Oak, Michigan.
CHAARTED (NCT00309985)1 showed that patients with metastatic, hormone-sensitive prostate cancer (mHSPC) lived significantly longer if they received docetaxel chemotherapy in addition to ADT. This finding was confirmed by the STAMPEDE trial (NCT00268476), which studied men with high-risk, locally advanced, metastatic, or recurrent prostate cancer.2
Several trials followed that assessed combinations of novel hormone therapies, including LATITUDE (NCT01715285), and demonstrated the benefits of combination therapy compared with ADT alone in metastatic castration-sensitive prostate cancer (mCSPC).3
“LATITUDE looked at a combination of abiraterone [Zytiga] and androgen deprivation therapies in high-risk patients to improve survival. And that has just been followed by the other oral therapies: apalutamide [Erleada] (TITAN, [NCT02489318]) and enzalutamide [Xtandi] (ARCHES [NCT0267789], ENZAMET [NCT02446405]) when used in combination in [patients with] mCSPC,” Hafron said.
These and other studies have led to widespread acceptance of treatment intensification in advanced prostate cancer. The National Comprehensive Cancer Network now “strongly recommend[s]…ADT with systemic treatment intensification…for most patients with metastatic CSP.”4 And the European Society for Medical Oncology (ESMO) recently updated its treatment recommendations for prostate cancer to include treatment intensification regimens.5
National Data Surveys show that many urologists and oncologists continue to prescribe ADT only. “It’s pretty depressing,” said Hafron, whose published study looked at claims data from 2015 to 2021 for nearly 67,000 men in the US with newly diagnosed mCSPC.6
On average, 25% of men were prescribed novel hormone therapy and 12%, chemotherapy. Oncologists were more likely to prescribe novel hormone therapy, at 32%, in the first-line setting, whereas urologists did so only 12% of the time, according to the study.
Putting changes into practice takes time, but that’s probably not the sole reason for the slow uptake of treatment intensification, according to Rana R. McKay, MD, a medical oncologist and associate professor of medicine at the University of California, San Diego School of Medicine. McKay authored “Treatment Intensification for Low-risk Metastatic Hormone-sensitive Prostate Cancer: The Time Is Now,” published November 2022 in European Urology Open Science.7
“Given the overwhelming evidence from transformative large phase 3 trials to support treatment intensification for patients with metastatic hormone-sensitive prostate cancer,” McKay said, “we need to understand the barriers to adoption.” These include concerns about data generalizability, side effects, tolerability, and cost—as well as a lack of awareness about the degree of benefit treatment intensification confers.
The reality is that with androgen-receptor signaling inhibitors like abiraterone, apalutamide, and enzalutamide, most patients with metastatic disease benefit, including “patients…[with] low- and high-volume [disease] and those…with de novo disease. The subgroup where the effect size is smaller is in the subset of patients with low-volume metachronous disease, given that these patients have a longer survival, need to be followed for a longer period of time, and are likely to receive subsequent treatments to control their disease,” she said.
Abhinav Sidana, MD, MPH, associate professor of surgery at the University of Cincinnati College of Medicine and director of Urologic Oncology at UC Medical Center in Ohio, is selective when it comes to treatment intensification. He sees patients with low-volume disease and refers those with very high-volume disease to medical oncology for chemotherapy.
“These drugs are relatively safe and, while they have complications, they’re not that difficult to manage,” he said. “It gives me a very rewarding experience…. I see patients with low-grade prostate cancer and when they become advanced prostate cancer, I already have a good relationship with them and don’t have to send them somewhere else.”
The outcomes are also rewarding because patients are living significantly longer with treatment intensification. “I’ve been in practice for only 6 years, and a lot of my patients are still on the first-line therapy. When I was a resident and we were treating only with ADT monotherapy, these patients would fail like clockwork in 2 years. Now, I have these patients on treatment for 4 to 5 years,” Sidana said.
According to Hafron, urologists who want to treat patients with advanced prostate cancer should keep abreast of the literature and guidelines because things are changing fast. “Up to a year ago, combination therapy was the standard of care, but if you look at the most recent NCCN guidelines, we see the introduction of triplet therapy, which is a combination of androgen deprivation therapy, chemotherapy (docetaxel), and oral novel hormone therapy (darolutamide [Nubeqa] or abiraterone),” he said.
Data from PEACE1 (NCT01957436) and ARASENS (NCT02799602), both phase 3 trials, showed even better overall survival (OS) with triplet therapy (docetaxel + ARSI + ADT) than with docetaxel and ADT, making the triplet the new standard of care for patients with mHSPC, particularly in high-volume and de novo disease.8
The ARASENS study examined the efficacy and safety of darolutamide added to ADT and docetaxel in patients with mHSPC. Among the 1306 patients randomly assigned (1:1) to receive darolutamide or matching placebo—both in combination with ADT and docetaxel—the risk of death was 32.5% lower in the darolutamide group.9,10
But triplet therapy is not the only newer approach to treating advanced prostate cancer. “We’re also seeing treatment intensification in metastatic castrate-resistant prostate cancer [mCRPC] using novel drug combinations to improve outcomes,” Hafron said. “In the last year or so, there have been 3 major trials that have looked at poly-adenosine diphosphate-ribose polymerase (PARP) inhibitors plus novel hormone therapies in combination.”
Those trials were PROpel (NCT03732820),11 MAGNITUDE (NCT03748641), and TALAPRO-2 (NCT03395197).12
“In 2 of the trials, PROpel and TALAPRO-2, we saw an improvement in progression-free survival for all patients, regardless of their mutation history (homologous recombination repair mutation (HRRm). However, when you looked at the MAGNITUDE trial, there was 1 arm where patients didn’t have the mutation, and that cohort ended early because there was a limited response,” Hafron said. “These combination therapies have been approved in Europe for all comers—whether they have a mutation or not. Recently, the FDA regrettably approved combination PARP therapy [only] in patients…with BRCA mutations for first-line therapy in mCRPC.”
Although urologists can manage many of the common adverse events (AEs) associated with the additional agents, according to McKay, things can get complicated.
With abiraterone, for example, there is the risk of mineralocorticoid excess, which can result in hypertension, low serum potassium, swelling, and liver function elevation and require monitoring. But if well-monitored, patients can do quite well with abiraterone plus low-dose prednisone, she said.
“For the androgen receptor blockers, like enzalutamide and apalutamide, there is less laboratory monitoring and no concurrent steroids, but there are some side effects to track, including fatigue,” she explained, and “there can be an increased risk for falls and fractures.”
The good thing about docetaxel is that the therapy is finite. Usually patients receive up to 6 cycles and are done with treatment in about 4 months. However, docetaxel comes with AEs like cytopenia, infection, peripheral neuropathy, swelling, and pneumonitis, although the latter is rare, McKay observed. “It’s a very common chemotherapy that we’ve been using…since 2004, and there is good expertise in how to manage…side effects,” she said.
On the other hand, systemic treatment options in the metastatic castration-resistant setting are more complex. “We have biomarker-directed therapies based on genomic profiling from the tumor and germline,” she said, and “considerations in this setting include chemotherapy, whether it be docetaxel or potentially cabazitaxel [Jevtana]. It includes radioligand therapy, whether that be radium 223 [Xofigo] or lutetium-177 prostate-specific membrane antigen [Pluvicto]. It includes immunotherapy with sipuleucel-T [Provenge] in select patients and pembrolizumab [Keytruda] for patients with microsatellite instability-high tumors or high tumor mutation burden. Then, of course, we also have olaparib [Lynparza] and rucaparib [Rubraca], which are PARP inhibitors approved for homologous recombination repair-deficient metastatic castration-resistant prostate cancer.”
The TRITON3 trial (NCT02975934) looked at about 400 participants with mCRPC and tumors with mutations in the BRCA1, BRCA2, or ATM genes. At 11.2 months, progression-free survival (PFS) was nearly twice as long with rucaparib than with any of the 3 other drugs commonly used for this form of prostate cancer (6.4 months).13
The FDA approval of olaparib was based on results from the PROfound trial (NCT02987543), which enrolled men with alterations in the BRCA1, BRCA2, or ATM genes or alterations in a group of 12 other genes involved DNA repair. All the men had cancer that had worsened despite treatment with abiraterone or enzalutamide, according to the National Cancer Institute.14
The nearly 400 men in the trial received either olaparib, abiraterone, or enzalutamide. Those treated with olaparib lived more than twice as long, at a median 7.4 months, without evidence of progression, compared with those treated with abiraterone and enzalutamide. The olaparib group also had better OS and improved tumor response.
All patients with metastatic disease, be it castration-sensitive or castration-resistant, should “undergo germline testing, given a hereditary risk of cancer that’s probably on the order of 10% to 12% in the metastatic setting,” McKay advised. “The reason to do germline testing is [because] it’s…predictive and can…help…individual patient[s] with treatment selection. It can help with screening for alternate cancers, and it can help with cascade testing,” she said.
McKay also recommends somatic tumor profiling for all patients with metastatic disease to identify those eligible for PARP inhibitors or immunotherapy. “The other thing about genetic testing is that patients can develop acquired mutations over time, so it’s…not unreasonable to repeat somatic tumor profiling tests after somebody…[is] exposed to certain therapies and develops progression to identify new mutations that might be targeted,” she said.
According to Margulis, the field has been moving steadily toward treatment intensification over the past decade and continues to evolve. “We need to start getting away from single or even double modality therapy for these patients and understand that the management of these patients will be driven by understanding specific molecular alterations that are inherent in their disease and tailoring their treatment to those alterations, such as in the case of PARP inhibitors which are suitable for certain patient populations with advanced prostate cancer,” Dr. Margulis said.
Because advanced prostate cancer is the most lethal cancer urologists are likely to see in the clinic—even worse than muscle invasive bladder cancer or advanced renal cell cancer—if they don’t specialize in it, they “should make sure these patients are referred to the appropriate specialists,” Hafron said.
1. 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
2. James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016;387(10024):1163-1177. doi:10.1016/S0140-6736(15)01037-5
3. Fizazi K, Tran N, Fein L, et al; LATITUDE Investigators. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377(4):352-360. doi:10.1056/NEJMoa1704174
4. Schaeffer E, Srinivas S, Antonarakis ES, et al. NCCN Guidelines Insights: Prostate cancer, version 1.2021. J Natl Compr Canc Netw. 2021;19(2):134-143. doi:10.6004/jnccn.2021.0008
5. Fizazi K, Gillessen S. Updated treatment recommendations for prostate cancer from the ESMO Clinical Practice Guideline considering treatment intensification and use of novel systemic agents. Ann Oncol. Published online March 21, 2023. doi:10.1016/j.annonc.2023.02.015
6. Heath EI, Dyson GE, Cackowski FC, Hafron J, Powell I. Treatment intensification patterns and utilization in patients with metastatic castration-sensitive prostate cancer. Clin Genitourin Cancer. 2022;20(6):524-532. doi:10.1016/j.clgc.2022.06.017
7. McKay RR. Treatment intensification for low-risk metastatic hormone-sensitive prostate cancer: the time is now. Eur Urol Open Sci. 2022;45:41-43. doi:10.1016/j.euros.2022.09.009
8. Dzimitrowicz HE, Armstrong AJ. Triplet therapy: entering the metaverse of metastatic hormone-sensitive prostate cancer treatment. Eur Urol. 2022;82(6):599-601. doi:10.1016/j.eururo.2022.08.031
9. 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
10. 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
11. Study on olaparib plus abiraterone as first-line therapy in men with metastatic castration-resistant prostate cancer. ClinicalTrials.gov. Updated April 5, 2022. Accessed May 9, 2023. https://clinicaltrials.gov/ct2/show/NCT03732820
12. Talazoparib + enzalutamide vs. enzalutamide monotherapy in mCRPC (TALAPRO-2). ClinicalTrials.gov. Updated February 13, 2023. Accessed May 9, 2023. https://clinicaltrials.gov/ct2/show/NCT03395197
13. Fizazi K, Piulats JM, Reaume MN, et al; TRITON3 Investigators. Rucaparib or physician’s choice in metastatic prostate cancer. N Engl J Med. 2023;388(8):719-732. doi:10.1056/NEJMoa2214676
14. National Cancer Institute staff. FDA approves olaparib, rucaparib to treat prostate cancer.Cancer Currents blog. June 11, 2020. Accessed May 8, 2023.