mCRPC Treatment

June 26, 2020, marked the 20^th anniversary of the publication of the first working draft from the Human Genome Project. At a special White House event to commemorate the results of this 10-year public effort (it was really more like 50 years since the discovery of DNA, but I digress), then-President Bill Clinton called the project “the most wondrous map ever created by humankind”, and touted its promise to detect, prevent, and treat disease.  Obtaining that first sequence from one human cost about $2B and resulted from a massive global public/private partnership.

Localized Treatment – Optimizing Fractionation

Several trials have recently focused on delineating the optimal radiotherapy fractionation schedule for the primary treatment of prostate cancer. In 2016, efficacy results of the Dutch HYPRO trial were published, assessing hypofractionated radiotherapy compared with conventionally fractionated radiotherapy among patients with intermediate-risk to high-risk T1b-T4NX-N0MX-M0 localized prostate cancer.¹ Patients were assigned 1:1 to either hypofractionated radiotherapy of 64.6 Gy (19 fractions of 3.4 Gy, three fractions per week) or conventionally fractionated radiotherapy of 78.0 Gy (39 fractions of 2.0 Gy, five fractions per week) with a primary endpoint of relapse-free survival. There were 804 patients assessed in the intention-to-treat analysis, of which 407 were assigned hypofractionated radiotherapy and 397 were allocated to conventionally fractionated radiotherapy. Additionally, 67% of patients received concomitant androgen deprivation therapy (ADT) for a median duration of 32 months (IQR 10-44). Over a median follow-up of 60 months (IQR 51-69), treatment failure was reported in 21% of patients, including 20% in the hypofractionation group and 22% in the conventional fractionation group. The 5-year relapse-free survival was 80.5% (95% CI 75.7-84.4) for patients assigned hypofractionation and 77.1% (71.9-81.5) for those allocated conventional fractionation (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.63-1.16; log-rank p=0.36). Based on these results, the authors noted that this current regimen of hypofractionated radiotherapy was not superior to conventional radiotherapy.

The CHHiP trial was a multi-center, randomized, Phase III trial, designed as a non-inferiority clinical trial, randomizing men with pT1b-T3aN0M0 prostate cancer 1:1:1 to conventional (74 Gy delivered in 37 fractions over 7.4 weeks) or one of two hypofractionated schedules (60 Gy in 20 fractions over 4 weeks or 57 Gy in 19 fractions over 3.8 weeks) all delivered with intensity-modulated techniques.² Most patients were given radiotherapy with 3-6 months of neoadjuvant and concurrent androgen suppression. The primary endpoint was time to biochemical or clinical failure, and the critical hazard ratio for non-inferiority was 1.208. In this large trial, 3,216 men were enrolled from 71 centers and randomly assigned: 1,065 patients to the 74 Gy group, 1,074 patients to the 60 Gy group, and 1,077 patients to the 57 Gy group. The median follow-up was 62.4 months (IQR 53.9-77.0) over which the proportion of patients who were biochemical or clinical failure-free at five years was 88.3% (95% CI 86.0-90.2) in the 74 Gy group, 90.6% (95% CI 88.5-92.3) in the 60 Gy group, and 85.9% (95% CI 83.4-88.0) in the 57 Gy group. The 60 Gy hypofractionated schedule was non-inferior to the conventional 74 Gy schedule (HR 0.84, 90% CI 0.68-1.03, p noninferiority = 0.0018), but non-inferiority was not possible for 57 Gy hypofractionation compared with 74 Gy (HR 1.20, 90% CI 0.99-1.46, p noninferiority = 0.48). 

Based on these initial studies, recent interest has related to even more intense radiotherapy fractionation. The Scandinavian HYPO-RT-PC randomized controlled Phase III trial was initially presented at ESTRO 2018, and subsequently published in Lancet Oncology.³ This trial randomized men with intermediate and high-risk prostate cancer to either conventional fractionating (n = 602; 78.0 Gy in 39 fractions, 5 days per week for 8 weeks) or ultrahypofractionated (n=598; 42.7 Gy in seven fractions, three days per week for 2.5 weeks). The primary endpoint was time to biochemical or clinical failure. The estimated failure-free survival at five years was 84% (95% CI 80-87) in both treatment groups, with an adjusted HR of 1.002 (95% CI 0.758-1.325; log-rank p=0.99). There was weak evidence of an increased frequency of acute physician-reported RTOG grade 2 or worse urinary toxicity in the ultra-hypofractionation group at end of radiotherapy (158 [28%] of 569 patients vs 132 [23%] of 578 patients; p=0.057). Based on these results, there has been support for the use of ultra-hypofractionated radiotherapy for prostate cancer.

However, despite encouraging results regarding biochemical/relapse-free survival as described above, studies have not demonstrated an overall survival (OS) benefit. Patients in the NRG Oncology RTOG 0126 trial that had intermediate-risk prostate cancer were randomized to 3-dimensional conformal radiation therapy or intensity-modulated radiation therapy to 79.2 Gy in 44 fractions or 70.2 Gy in 39 fractions.⁴ Over a median follow-up of 8.4 years in 1,499 patients, there was no difference in OS between the 751 men in the 79.2-Gy arm and the 748 men in the 70.2-Gy arm. The 8-year rates of OS were 76% with 79.2 Gy and 75% with 70.2 Gy (HR 1.00, 95% CI, 0.83-1.20), and the 8-year cumulative rates of distant metastases were 4% for the 79.2-Gy arm and 6% for the 70.2-Gy arm (HR 0.65, 95% CI, 0.42-1.01). As the above trials continue to mature, it will be imperative to evaluate survival outcomes. However, adoption of hypofractionation needn’t require improved survival or toxicity outcomes – on the basis of equivalence, improvements in the patient experience/convenience and cost would support the adoption of this approach.

Localized Disease – Optimizing Androgen Deprivation Therapy (ADT)

A second initiative of recent radiotherapy trials has been delineating the appropriate dose of ADT given concurrently with radiotherapy. The DART01/05 GICOR trial was a randomized, controlled Phase III trial assessing high-dose radiotherapy with short-term or long-term ADT for patients with T1c-T3b N0M0 prostate cancer with intermediate-risk and high-risk features.⁵ Patients were randomly assigned 1:1 to receive either four months of ADT combined with three-dimensional conformal radiotherapy at a minimum dose of 76 Gy (range 76-82 Gy; short-term ADT group) or the same treatment followed by 24 months of adjuvant ADT (long-term ADT group), stratified by prostate cancer risk group (intermediate risk vs high risk). In this Spanish multi-center trial, 178 patients were randomly assigned to receive short-term ADT and 177 to receive long-term ADT. After a median follow-up of 63 months (IQR 50-82), 5-year biochemical disease-free survival was significantly better among patients receiving long-term ADT than among those receiving short-term ADT: 90% (95% CI 87-92) vs 81% (95% CI 78-85), HR 1.88, 95% CI 1.12-3.15. Furthermore, the 5-year OS (95% vs 86%; HR 2.48, 95% CI 1.31-4.68) and 5-year MFS (94% vs 83%; HR 2.31, 95% CI 1.23-3.85) rates were also significantly better in the long-term ADT group than in the short-term ADT group. Not surprisingly, the authors noted that the effect of long-term ADT on biochemical disease-free survival, metastasis-free survival, and overall survival was more evident in patients with high-risk disease than in those with low-risk disease. 

In 2016, the results of the EORTC 22991 randomized trial were published.⁶ This trial assessed if biochemical disease-free survival (DFS) is improved by adding six months of androgen suppression to primary radiotherapy for intermediate- or high-risk localized prostate cancer. Among 819 patients, the median patient age was 70 years, 74.8% were intermediate risk and 24.8% were high risk. At 7.2 years median follow-up, radiotherapy plus androgen suppression significantly improved biochemical DFS (HR 0.52, 95% CI 0.41-0.66), as well as clinical progression-free survival (HR 0.63, 95% CI 0.48-0.84).

Long-term follow-up of the D’Amico trial assessing ADT plus radiotherapy versus ADT alone for patients with localized, unfavorable risk prostate cancer was published in 2015⁷. This analysis importantly showed that underlying comorbidity significantly modified the benefit of ADT: in patients with moderate or severe comorbidity, use of radiotherapy alone was associated with decreased cardiac mortality (HR 0.17, 95% CI 0.06-0.46), non-prostate cancer mortality (HR 2.79, 95% CI 1.02-7.60), and overall mortality (HR 0.36, 95% CI 0.19-0.67). Conversely, in men with no or minimal comorbidity, radiotherapy alone was associated with an increased risk of overall mortality and prostate cancer mortality, without coinciding decreases in cardiac mortality or non-prostate cancer mortality.

The prior standard ADT duration was 28-36 months when combined with radiotherapy for high-risk disease. As such, the TROG RADAR trial assessed whether the addition of 12 months of adjuvant ADT, 18 months of zoledronic acid, or both, can improve outcomes in men with locally advanced prostate cancer who receive six months of ADT and prostate radiotherapy.⁸ In 2019, this trial reported 10-year outcomes. There were 1,071 patients randomized to radiotherapy plus six months of ADT or radiotherapy plus 18 months of ADT. This trial found that 18 months of ADT plus radiotherapy is a more effective treatment option for locally advanced prostate cancer than six months of ADT plus radiotherapy (HR 0.70, 95% CI 0.50-0.98), but the addition of zoledronic acid to this treatment regimen is not beneficial. Finally, the PCS IV Trial randomized 630 patients with a median follow-up of 9.4 years to radiotherapy plus 18 months of ADT or radiotherapy plus 36 months of ADT.⁹ The 5-year OS rates were 91% for long term ADT arm (95% CI 88-95%) and 86% for short term ADT arm (95% CI 83-90%, p=0.07). The quality of life analysis showed a significant difference (p<0.001) in six scales and 13 items favoring 18 months of ADT.           

Localized Disease – Addition of Chemotherapy

The benefit of adding chemotherapy in the treatment of very high-risk disease has also been recently evaluated. Rosenthal et al.¹⁰ published the multicenter randomized NRG Oncology RTOG 0521 clinical trial, which enrolled patients with high-risk nonmetastatic disease between 2005 and 2009. Patients were randomly assigned (n=563) to receive standard long-term ADT plus radiotherapy with or without adjuvant chemotherapy. Over a median follow-up of 5.7 years, the 4-year OS rate was 89% (95% CI, 84% to 92%) for ADT and radiotherapy, compared to 93% (95% CI, 90% to 96%) for ADT and radiotherapy plus chemotherapy (HR 0.69, 90% CI 0.49-0.97). Six-year rate of distant metastasis was 14% for ADT and radiotherapy and 9.1% for ADT and radiotherapy plus chemotherapy, (HR 0.60, 95% CI 0.37-0.99).

Treatment after Radical Prostatectomy

For decades, urologists and radiation oncologists have debated the optimal timing, location, and dose of radiotherapy, in addition to the utilization of ADT among those experiencing biochemical recurrence after radical prostatectomy. The much-anticipated NRG Oncology/RTOG 0534 SPPORT trial reported initial results at the 2019 ASTRO meeting.¹¹ This trial randomized 1,736 patients to either (i) salvage radiotherapy to the prostate bed, (ii) salvage radiotherapy to the prostate bed plus ADT, or (iii) salvage radiotherapy to the prostate bed plus ADT plus radiotherapy to the pelvic lymph nodes. The 5-year freedom from progression rate was 71% for salvage radiotherapy to the prostate bed, 81% for salvage radiotherapy to the prostate bed plus ADT, and 87% for salvage radiotherapy to the prostate bed plus ADT plus radiotherapy to the pelvic lymph nodes. Based on only 108 patients with metastasis, there were minimal differences between the three arms with regards to metastasis-free survival. It is likely that with continued follow-up, these results will likely continue to favor salvage radiotherapy to the prostate bed plus ADT plus radiotherapy to the pelvic lymph nodes.

Previously, Shipley et al. assessed whether antiandrogen therapy with radiation therapy improves cancer control and prolong OS among patients with biochemical recurrence.¹² In this trial, there were 760 patients who had undergone radical prostatectomy with lymphadenectomy and had biochemically recurrent disease who were randomized to radiation therapy and to receive either antiandrogen therapy (24 months of bicalutamide at a dose of 150 mg daily) or daily placebo tablets during and after radiation therapy. The primary endpoint was the OS rate; the actuarial rate of OS at 12 years was 76.3% in the bicalutamide group, as compared with 71.3% in the placebo group (HR 0.77, 95% CI 0.59 to 0.99). The 12-year incidence of death from prostate cancer was 5.8% in the bicalutamide group, as compared with 13.4% in the placebo group (p < 0.001). Finally, the cumulative incidence of metastatic prostate cancer at 12 years was 14.5% in the bicalutamide group, as compared with 23.0% in the placebo group (p = 0.005). As such, the addition of antiandrogen improved clinical outcomes and OS in patients with biochemical recurrence after radical prostatectomy.

Several randomized trials assessing adjuvant vs salvage radiotherapy have been presented earlier this year at academic conferences, but have yet to be published. 

Radiotherapy in the Setting of Metastatic Disease

Several trials have recently assessed the impact of radiotherapy to the prostate in the setting of metastatic disease, given retrospective evidence that patients may derive a survival benefit for treatment to the primary prostate tumor. The HORRAD trial was a multi-center randomized controlled trial recruiting 432 patients with a prostate-specific antigen (PSA) >20ng/ml and primary bone metastatic prostate cancer on bone scan (between 2004 and 2014).¹³ Patients were randomized to either ADT with external beam radiotherapy or ADT alone. The median PSA level was 142ng/ml and 67% of patients had more than five osseous metastases. Over a median follow up of 47 months, the median OS was 45 months (95% CI, 40.4-49.6) in the radiotherapy group and 43 months (95% CI, 32.6-53.4) in the control group (p = 0.4; HR 0.90, 95% CI 0.70-1.14). The median time to PSA progression in the radiotherapy group was 15 months (95% CI, 11.8-18.2), compared with 12 months (95% CI, 10.6-13.4) in the control group.

Despite the negative results from HORRAD, there was much anticipation for the results of the STAMPEDE arm H clinical trial assessing the efficacy of radiotherapy to the primary in M1 disease.¹⁴ This study randomized 2,061 to either standard systemic treatments (ADT +/- chemotherapy) versus standard systemic treatments (ADT +/- chemotherapy) plus radiotherapy to the primary. There were 819 (40%) men that had a low metastatic burden, 1,120 (54%) had a high metastatic burden, and the metastatic burden was unknown for 122 (6%). Radiotherapy improved failure-free survival (HR 0.76, 95% CI 0.68-0.84) but not OS (HR 0.92, 95% CI 0.80-1.06). In a prespecified subgroup analysis, patients receiving radiotherapy to the prostate among patients with low metastatic burden, there was a significant improvement in OS (HR 0.68, 95% CI 0.52-0.90).

The SABR-COMET trial was an important trial published in 2019 assessing stereotactic body radiotherapy to oligometastatic disease.¹⁵ The objective of this study was to assess the standard of care of palliative treatments with or without stereotactic body radiotherapy in up to five metastatic lesions. The trialist’s hypothesis was that patients with oligometastatic disease will have improved outcomes with treatment of their metastatic sites. This study included any cancer (primarily breast, prostate, colorectal, and lung) who were then randomized 1:2 to standard of care versus standard of care plus stereotactic body radiotherapy. The standard of care was at the discretion of the physician and the primary endpoint was OS. There were 99 patients at 10 centers and median follow-up was 25.5 months. Median OS was 28 months (95% CI 19-33) in the control group versus 41 months (26-not reached) in the stereotactic body radiotherapy group (HR 0.57, 95% CI 0.30-1.10; p =0.090). Adverse events of grade 2 or worse occurred in three (9%) of 33 controls and 19 (29%) of 66 patients in the stereotactic body radiotherapy group (p=0.026), an absolute increase of 20% (95%CI 5-34). Treatment-related deaths occurred in three (4.5%) of 66 patients after stereotactic body radiotherapy, compared with none in the control group. The authors concluded that stereotactic body radiotherapy was associated with a 13-month increase in OS and doubling of progression-free survival (PFS).

Conclusions

The last five years have seen several important and practice-changing clinical trials for the treatment of prostate cancer with radiotherapy. Early results suggest that ultra-hypofractionation may make primary treatment with radiotherapy an attractive, less arduous option, however long-term OS results for hypofractionation will be important. There is little doubt that the addition of ADT to radiotherapy in high-risk patients for primary treatment and those experiencing biochemical failure after radical prostatectomy improves outcomes. Furthermore, based on results from the STAMPEDE Arm H clinical trial, many clinicians are now treating the prostate primary among men with low-volume metastatic disease. Finally, ongoing studies utilizing stereotactic body radiotherapy to metastatic sites will be important as we focus on improving quality as well as quantity of life for patients with advanced, heavily treated prostate cancer.

Published Date: January 2020

Germline testing indications for prostate cancer (PCa) have rapidly expanded and have been catapulted by precision medicine and precision management.^1,2 In particular, testing for mutations in DNA repair genes such as in BRCA2, BRCA1, ATM, and other DNA repair genes, has taken front-stage due to the clinical activity of poly (ADP-ribose) polymerase (PARP) inhibitors in metastatic, castration-resistant prostate cancer (mCRPC).^3-7 Phase II trial data supported the U.S. Federal Drug Administration (FDA) designations for olaparib, rucaparib, and niraparib due to demonstrated response rates particularly among men with BRCA2 mutations along with other DNA repair genes.^5-7 Excitingly, the FDA has recently approved two PARP inhibitors for mCRPC. Rucaparib was granted accelerated approval for BRCA1/2-mutated mCRPC with prior treatment with androgen receptor-directed therapy and taxane-based chemotherapy based on TRITON2.⁵ Olaparib was FDA-approved for the treatment of mCRPC in men with deleterious or suspected deleterious germline or somatic homologous recombination repair gene mutations who have progressed following prior treatment with enzalutamide or abiraterone based on PROfound.⁴ These approvals provide exciting therapeutic options for men with mCRPC and will increase the role of germline testing for DNA repair mutations. Furthermore, the National Comprehensive Cancer Network (NCCN) guidelines recommend germline testing for DNA repair mutations in all men with mCRPC, with additional testing criteria proposed.^8,9 The international Philadelphia Prostate Cancer Consensus Conference 2019 has provided significant multidisciplinary guidance regarding germline testing for DNA repair mutations across the stage spectrum, along with strategies for implementation of genetic counseling and germline testing.¹ Therefore, understanding the role of germline testing in PCa is now critical to urologic and oncology practice for this disease. Here, we will address who should be considered for germline testing, when germline testing may influence treatment and management, and how to implement germline testing involving provider practices and genetic counseling.

Zoledronic acid

Second-line treatment options for metastatic castrate-resistant prostate cancer

Cabazitaxel

Figure 1. TROPIC study design

Abiraterone following docetaxel

Figure 4

Changing and sequencing treatment in metastatic castrate-resistant prostate cancer

Radioligand therapy for metastatic castrate-resistant prostate cancer patients

Treatment and prevention of skeletal-related events

Future and ongoing trials

1. The combination of abiraterone and Olaparib as first-line therapy in mCRPC patients (NCT03732820)
2. A study assessing the role of Rucaparib (a PARP inhibitor) vs. physician’s choice therapy in mCRPC patients (TRITON3 trial - NCT02975934)
3. The combination of pembrolizumab with various other medications including enzalutamide (NCT03834493 - as part of the MK-3475-641/KEYNOTE-641 trial), docetaxel (NCT03834506 - as part of the MK-3475-921/KEYNOTE-921 trial), and olaparib (NCT03834519 – as part of the MK-7339-010/KEYLYNK-010)
4. The ACIS trial, which will assess the combination of apalutamide, and abiraterone + prednisone in mCRPC patients (NCT02257736)
5. A study assessing Masitinib (a tyrosine kinase inhibitor) plus docetaxel (NCT03761225)
6. The combination of Talazoparib (a PARP inhibitor) + plus enzalutamide (NCT03395197),
7. The combination of Atezolizumab (an anti-PD-L1 monoclonal antibody) + enzalutamide (NCT03016312)
8. The combination of docetaxel and Radium-223 (NCT03574571)
9. A study assessing 177Lu-PSMA-617 in mCRPC patients (NCT03511664)
10. The IPATential150 trial – assessing the combination of Ipatasertib (an orally administered, ATP-competitive, selective AKT inhibitor) plus abiraterone (NCT03072238)

Conclusions

What are the most common genomic aberrations seen in DNA damage response (DDR) pathways in advanced prostate cancer?

Approved first-line treatment options for metastatic castrate-resistant prostate cancer

Abiraterone

Figure 1

Enzalutamide

Figure 2

Docetaxel

Figure 3

Sipuleucel-T

Conclusions

Prostate cancer is a clinically heterogeneous disease with many patients having an indolent course requiring no interventions and others who either present with or progress to metastasis. While underlying dominant driving mutations are not widespread, there have been a number of key genomic mutations that have been consistently identified in prostate cancer patients, across the disease spectrum including gene fusion/chromosomal

Introduction and Epidemiology

The Biology of Visceral Metastases

Impact of Visceral Metastases on Survival

Radioligand Therapy for mCRPC Patients

Conclusions  

Despite warranted concerns regarding the overdiagnosis and overtreatment of many cases of biologically indolent prostate cancer, prostate cancer remains the second leading cause of cancer-related death in the United States behind only lung cancer.¹ With current treatment paradigms, nearly all patients who die of prostate cancer first receive androgen-deprivation therapy and then progress to castrate-resistant prostate cancer.